WO2012098281A2 - Peptides modulateurs de récepteurs trp et leurs utilisations - Google Patents

Peptides modulateurs de récepteurs trp et leurs utilisations Download PDF

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Publication number
WO2012098281A2
WO2012098281A2 PCT/ES2012/070026 ES2012070026W WO2012098281A2 WO 2012098281 A2 WO2012098281 A2 WO 2012098281A2 ES 2012070026 W ES2012070026 W ES 2012070026W WO 2012098281 A2 WO2012098281 A2 WO 2012098281A2
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Prior art keywords
peptide
seq
pain
agents
amino acids
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PCT/ES2012/070026
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English (en)
Spanish (es)
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WO2012098281A3 (fr
Inventor
Antonio Ferrer Montiel
Asia Fernández Carvajal
Gregorio FERNÁNDEZ BALLESTER
José Manuel GONZÁLEZ ROS
Carlos BELMONTE MARTÍNEZ
Pierluigi VALENTE
María CAMBPRUBI ROBLES
Félix VIANA DE LA IGLESIA
Ana GOMIS GARCÍA
Wim Van Den Nest
Cristina CARREÑO SERRAÏMA
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Universidad Miguel Hernández De Elche
Bcn Peptides, S.A.
Consejo Superior De Investigaciones Científicas
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Publication of WO2012098281A2 publication Critical patent/WO2012098281A2/fr
Publication of WO2012098281A3 publication Critical patent/WO2012098281A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates to peptides that have the ability to modulate the activity of TRP receptors and their uses. More specifically, the authors of the invention have identified peptide inhibitors that are capable of specifically binding to TRPV1, TRPM8 and / or TRPA1 thermoreceptors and inhibiting the activity of said receptors.
  • Nociceptive neurons recognize mechanical, thermal and chemical stimuli that can be harmful to the body. Therefore, they are considered guardians of tissue integrity and nociception an essential safety mechanism for life. At the molecular level, they have in their terminals a set of protein receptors prepared to recognize and transduce harmful physical (mechanical, osmotic and thermal) and chemical stimuli. In this sense, the human being has receptors capable of recognizing the spectrum of temperatures from very cold ( ⁇ 17 ° C) to very hot (> 50 ° C) [Belmonte et al. (2008) Mol. Pain 4: 14].
  • TRP Transient Potential Receptors
  • TRPC Transient Potential Receptors
  • TRPM Transient Potential Receptors
  • TRPV Transient Potential Receptors
  • TRPA Transient Potential Receptor
  • TRPP Transient Potential Receptor
  • TRPML Transcription regulator
  • TRPN present in invertebrates
  • TRPY in yeasts
  • TRP receptors play a fundamental role in the transduction of the different somatosensory modalities, including thermosensing, pheromone reception, vascular tone regulation, nociception and pain. It is increasingly clear that TRP receptors are very important in sensory physiology and that their functional alteration, either by mutations or by harmful stimuli or pro-inflammatory factors, leads to pathological states in humans.
  • TRP receptors are expressed in a wide variety of multicellular organisms comprising yeasts, worms, fruit flies, zebrafish, and mammals. All TRP receptors are cationic channels that allow the flow of Ca 2+ and Na + , although according to the isoform the permeability and selectivity with respect to mono or divalent cations varies substantially. Its pattern of tissue distribution is very wide, appearing expressed in virtually all tissues, especially in the central and peripheral nervous systems, in which they play a crucial role in sensory transduction, converting environmental stimuli into changes in neuronal membrane excitability [Venkatachalam K. et al. (2007) Annu. Rev. Biochem. 76: 387-417].
  • TRPP TRPP family
  • TRPML TRPML
  • TRPC6 segmental glomerulosclerosis
  • TRPM6 mutation causes hypomagnesemia and hypocalcaemia [Venkatachalam K. et al. cited ad supra].
  • the TRPV subfamily Transient Potential Receptors activated by
  • Vanilloides in mammals is made up of 6 members divided into 2 groups according to the degree of homology, TRPV1 -4 and TRPV5-6.
  • the TRPV1 receptor has become a crucial target in the transduction of painful signals, especially in the etiology of inflammatory pain.
  • TRPV1 participates in the onset and maintenance of neurogenic inflammation that usually accompanies tissue damage.
  • the genetic or pharmacological elimination of the receptor in animals produces a reduction of the inflammatory process that translates into an attenuation of thermal hyperalgesia [Venkatachalam K. et al. cited ad supra].
  • thermoreceptors involved in cold sensitivity are TRPA1, which is activated at temperatures below 17 ° C, and TRPM8, which is activated at temperatures below 30 ° C.
  • TRPA1 which is activated at temperatures below 17 ° C
  • TRPM8 which is activated at temperatures below 30 ° C.
  • TRPV1 is overexpressed in asthma as well as in other diseases or inflammatory disorders of the respiratory tract, while the early inflammatory response to cigarette smoke is mediated. completely due to the activity of neuronal TRPA1 [Nassini R. et al. (2010) Curr. Opin. Investig. Drugs 1 1: 535-542].
  • TRPM8 induces the release of histamine by mast cells, which contributes to the development of allergic responses of the respiratory tract, such as asthma [Cho Y. et al. (2010) Cell Calcium 48: 202-208].
  • TRPV1, TRPA1 and / or TRPM8 antagonists therefore have potential application as antitussives, antiallergics and / or anti-inflammatories for the treatment and / or prevention of respiratory tract diseases.
  • the TRPM8 receptor seems to be involved in the development of cancer, because its levels are markedly elevated in the cancer cells of prostate and pancreas cancer. Inhibitors of this receptor have shown anti-proliferative activity in cell cultures of prostate tumor cells [Knowlton W.M. et al. (2010) Curr. Pharm Biotechnol Nov 8; Yee N.S. et al. (2010) Cancer Lett. 297: 49-55; Bai V.U. et al. (2010) Int. J. Oncol. 36: 443-450].
  • the TRPV1, TRPA1 and TRPM8 receptors are calcium channels. Due to the important role that calcium regulation plays in many cellular processes, including cell activation, gene expression, cell traffic and cell death due to apoptosis, dishomeostasis or calcium imbalance is implicated in many diseases and disorders related to such activities. cell phones, such as dermatological diseases and disorders, Neurological, neurodegenerative, urological, intestinal, respiratory, digestive, metabolic, hepatic, renal, cancer and sensitivity to pain and touch. The flow of calcium through the plasma membrane of skin cells is a critical signaling element involved in cell differentiation in the skin epidermis [Dotto GP (1999) Crit. Rev. Oral Biol. Med. 10: 442-457].
  • the decrease in neuronal excitability, in particular the excitability of the C fibers by administration of TRPV1, TRPA1 and / or TRPM8 antagonists can alleviate the pruritus associated not only with diseases and disorders of the skin and / or mucous membranes but also the pruritus associated with other diseases or epithelial, gastrointestinal, cardiovascular system, urinary tract, endocrine, cerebral, reproductive system, respiratory tract and / or cancer disorders.
  • Nociceptive pain includes pain induced by tissue damage, such as a cut or a burn, and inflammatory pain, such as arthritis. It is due to the activation of pain-sensitive nerve fibers, both somatic and visceral. Nociceptive pain has been traditionally treated by the administration of non-opioid analgesics, including acetylsalicylic acid, choline, magnesium trisalicylate, acetaminophen / paracetamol, ibuprofen, fenoprofen, diflunisal and naproxen, among others.
  • non-opioid analgesics including acetylsalicylic acid, choline, magnesium trisalicylate, acetaminophen / paracetamol, ibuprofen, fenoprofen, diflunisal and naproxen, among others.
  • Neuropathic pain refers to pain induced by damage to the peripheral or central nervous system and is characterized by an aberrant somatosensory process [McQuay HJ (1997) Acta Anaesthesiol. Scand. 41: 175-183]. In contrast to the immediate pain caused by tissue damage, neuropathic pain may develop days or months after traumatic damage. Neuropathic pain is associated with chronic sensory discomforts that include pain. spontaneous, hyperalgesia ⁇ ie feeling more pain than the stimulus justifies) and allodynia (ie a condition in which non-painful conventional stimuli induce pain). In humans, prevalent symptoms include cold hyperalgesia and mechanical allodynia.
  • neuropathic pain syndromes include those due to the progression of a disease, such as diabetic neuropathy, multiple sclerosis or post-herpetic neuralgia; those initiated by harm, such as amputation; or prolonged damage in an accident (for example, avulsion); and those caused by nerve damage, such as chronic alcoholism, viral infection, hypothyroidism, uremia or vitamin deficiencies.
  • Neuropathic pain is often resistant to therapies with known medications.
  • Such therapies include opioids, antiepileptics, NMDA glutamate receptor antagonists and tricyclic antidepressants. However, none of these treatments is particularly effective. Also, pain can be classified as acute and chronic, depending on the duration of the pain.
  • TRP receptors are involved in both neuropathic and nociceptive pain.
  • TRPV1, TRPM8 and / or TRPA1 antagonists are capable of attenuating hyperalgesia, allodynia or mechanical hypersensitivity in models of inflammatory or neuropathic pain [DiMarzo V. et al. (2002) Curr. Opin. Neurobiol 12: 372-379; Eid S.R. et al. (2008) Mol. Pain 4:48; Gauchan P. et al. (2009) Neurosci. Lett. 458: 93-95].
  • TRPV1 and TRPA1 are overexpressed in painful gastrointestinal diseases, such as inflammatory bowel disease, Crohn's disease or colitis [Geppetti P. et al. (2004) Br. J. Pharmacol. 141: 1313-1320; Kimball ES et al. (2007) Neurogastroenterol. Motil 19: 390-400].
  • TRPV1, TRPM8 and TRPA1 have been identified in the urinary tract of humans and have been described as being involved in bladder distension [Lashinger ES et al. (2008) Am. J. Physiol. Renal Physiol.
  • TRPA1 is activated by stimulation of muscarinic acetylcholine type 1 receptors (M1 AChR) [Jordt SE et al. (2004) Nature 427: 260-265], and it is well known that antimuscarinic compounds are useful in the treatment of diseases or disorders of the urinary system such as overactive bladder, so that blocking TRPA1 could alleviate such conditions without the effects side effects that are associated with muscarinic antagonists.
  • M1 AChR muscarinic acetylcholine type 1 receptors
  • TRPV1 also seems to be involved in epithelial diseases or disorders, such as allergic contact dermatitis and also seems to have a cardioprotective role [Nilius B. et al. (2007) Physiol. Rev. 87: 165-217]. TRPA1 also plays a key role in the development of skin disorders [Atoyan R. et al. (2009) J. Invest. Dermatol 129: 2312-2315].
  • TRPV1, TRPM8 and TRPA1 as therapeutic targets and their involvement in a multitude of diseases and / or disorders that occur with pain, inflammation and / or pruritus or in diseases and / or disorders of the respiratory tract or related to calcium imbalances , have led to the development by the cosmetic and pharmaceutical industry of different activators and inhibitors of said receptors.
  • capsaicin which is used in topical applications for the treatment of different conditions (ALGRX 4975 from AlgoRx / Anesiva for localized injections or transaicin, originally NGX-4010 from Merck / Neurogen, in dermal patches ), resiniferatoxin, a toxin isolated from Euphorbia resin ⁇ fera, olvanil (originally NE-19550 from P&G), as well as the compounds SDZ-249482 and SDZ-249665 from Novartis, which have shown good efficacy in animal models of pain and inflammation [ Messeguer A. et al. (2006) Curr. Neuropharmacol 4: 1-9].
  • TRPA1 agonists include cinnamaldehyde, allyl isothiocinanate, diallyl disulfide, iciline, cinnamon oil, gaulteria oil, acrolein and mustard oil.
  • TRPM8 receptor activators include menthol, icicline, eucalyptol, linalool, geraniol and hydroxycitronellal.
  • TRP receptor agonists have been the development of antagonists that induce receptor inhibition without the described side effects associated with its activation.
  • the cosmetic and pharmaceutical sector have developed different antagonists of TRPV1, TRPM8 and / or TRPA1, such as for example and without limitation the compounds SB-705498 of GlaxoSmith-Kline, NGD-8243 of Merck / Neurogen, AMG-517 of Amgen, GRC -621 to Glenmark, capsacepin, 5-iodine-resiniferatoxin, methoctramine, or those described in WO 00/56761 A1, WO 02/30956 A1, WO 03/097670 A1, US 2009/0143377 A1, US 2009/0176883 A1 , US 2009/0264480 A1, WO 2010/004390 A1, US 2010/0137259 A1,
  • WO 2010/141805 A1 WO 2010/125469 A1, WO 2010/144680 A1, WO 2010/103381 A1, or US 2008/0287398 A1 among others. These antagonists are in different stages of development and currently none of those who have entered clinical studies have successfully completed them.
  • the invention relates to a peptide, hereinafter peptide of the invention, selected from the group consisting of:
  • peptide comprising the sequence SEQ ID NO: 1 or a functionally equivalent variant, where the length of said peptide is equal to or less than 25 amino acids and where the asparagine of the sequence SEQ ID NO: 1 remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 3 or a functionally equivalent variant, where the length of said peptide is equal to or less than 25 amino acids, the arginine and glutamine of SEQ ID NO: 3 remain unchanged and where the peptide is not the sequence peptide SEQ ID NO: 4;
  • (v) peptide comprising the sequence SEQ ID NO: 7 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the asparagine of SEQ ID NO: 7 closest to the C-terminal remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 8 or a functionally equivalent variant, wherein the length of said peptide is equal or less than 20 amino acids, and where the valine and / or tryptophan of SEQ ID NO: 8 remain unchanged;
  • peptide comprising the sequence SEQ ID NO: 9 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the isoleucine of SEQ ID NO: 9 remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 10 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the amino acid of the V-terminal / end of SEQ ID NO: 10 it can only be isoleucine or leucine, and the valine of said sequence remains unchanged;
  • (ix) peptide comprising the sequence SEQ ID NO: 1 1 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the histidine of SEQ ID NO: 1 1 remains unchanged;
  • (x) peptide comprising the sequence SEQ ID NO: 12 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the peptide is not the sequence peptide SEQ ID NO: 13;
  • the invention relates to a process for preparing the peptide of the invention, its stereoisomers, mixtures thereof and / or its cosmetically or pharmaceutically acceptable salts, characterized in that it is carried out in solid phase or in solution or is a combination. of solid phase and solution synthesis.
  • the invention relates to a cosmetic or pharmaceutical composition
  • a cosmetic or pharmaceutical composition comprising at least one peptide of the invention or a functionally equivalent variant, its stereoisomers, mixtures thereof and / or its cosmetically or pharmaceutically acceptable salts, together with at least a cosmetic or pharmaceutically acceptable adjuvant.
  • the invention relates to the use of at least one peptide selected from the group consisting of: (i) peptide comprising the sequence SEQ ID NO: 1 or a functionally equivalent variant, where the length of said peptide is equal to or less than 25 amino acids and where the asparagine of the sequence SEQ ID NO: 1 remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 3 or a functionally equivalent variant, where the length of said peptide is equal to or less than 25 amino acids and where the arginine and glutamine of the
  • (v) peptide comprising the sequence SEQ ID NO: 7 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the asparagine of SEQ ID NO: 7 closest to the C-terminal remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 8 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the valine and / or tryptophan of SEQ ID NO: 8 is they remain unchanged;
  • peptide comprising the sequence SEQ ID NO: 9 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the isoleucine of SEQ ID NO: 9 remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 10 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the amino acid of the V-terminal / end of SEQ ID NO: 10 it can only be isoleucine or leucine, and the valine of said sequence remains unchanged;
  • (ix) peptide comprising the sequence SEQ ID NO: 1 1 or a functionally equivalent variant, wherein the length of said peptide is equal or less than 20 amino acids, and where the histidine of SEQ ID NO: 1 1 remains unchanged;
  • (x) peptide comprising the sequence SEQ ID NO: 12 or a functionally equivalent variant, wherein the length of said peptide is equal to or less than 20 amino acids;
  • the invention relates to the use of at least one peptide selected from the group consisting of:
  • peptide comprising the sequence SEQ ID NO: 1 or a functionally equivalent variant, where the length of said peptide is equal to or less than 25 amino acids and where the asparagine of the sequence
  • peptide comprising the sequence SEQ ID NO: 3 or a functionally equivalent variant, where the length of said peptide is equal to or less than 25 amino acids and where the arginine and glutamine of SEQ ID NO: 3 remain unchanged;
  • (v) peptide comprising the sequence SEQ ID NO: 7 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the asparagine of SEQ ID NO: 7 closest to the C-terminal remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 8 or a functionally equivalent variant, wherein the length of said peptide is equal or less than 20 amino acids, and where the valine and / or tryptophan of SEQ ID NO: 8 remain unchanged;
  • peptide comprising the sequence SEQ ID NO: 9 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the isoleucine of SEQ ID NO: 9 remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 10 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the amino acid of the V-terminal / end of SEQ ID NO: 10 it can only be isoleucine or leucine, and the valine of said sequence remains unchanged;
  • (ix) peptide comprising the sequence SEQ ID NO: 1 1 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the histidine of SEQ ID NO: 1 1 remains unchanged;
  • (x) peptide comprising the sequence SEQ ID NO: 12 or a functionally equivalent variant, wherein the length of said peptide is equal to or less than 20 amino acids;
  • the invention relates to the use of at least one peptide selected from the group consisting of:
  • peptide comprising the sequence SEQ ID NO: 1 or a functionally equivalent variant, where the length of said peptide is equal to or less than 25 amino acids and where the asparagine of the sequence SEQ ID NO: 1 remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 3 or a functionally equivalent variant, wherein the length of said peptide is equal or less than 25 amino acids and where the arginine and glutamine of SEQ ID NO: 3 remain unchanged;
  • the invention relates to the use of at least one peptide selected from the group consisting of:
  • peptide comprising the sequence SEQ ID NO: 7 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the asparagine of SEQ ID NO: 7 closest to the C-terminal remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 8 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the valine and / or tryptophan of SEQ ID NO: 8 is they remain unchanged;
  • the invention relates to the use of at least one peptide selected from the group consisting of:
  • peptide comprising the sequence SEQ ID NO: 9 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the isoleucine of SEQ ID NO: 9 remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 10 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the amino acid of the V-terminal / end of SEQ ID NO: 10 it can only be isoleucine or leucine, and the valine of said sequence remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 1 1 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the histidine of SEQ ID NO: 1 1 remains unchanged;
  • the invention relates to the use of at least one peptide selected from the group consisting of:
  • peptide comprising the sequence SEQ ID NO: 7 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the asparagine of SEQ ID NO: 7 closest to the C-terminal remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 8 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the valine and / or tryptophan of SEQ ID NO: 8 is they remain unchanged;
  • FIG. 1 shows that the Palmitoil-SEQ ID NO: 16-NH 2 peptide inhibited the release of capsaicin-induced ⁇ -CGRP in rat sensory neurons.
  • the release of ⁇ -CGRP was induced by applying 1 ⁇ of capsaicin for 5 minutes.
  • Neural cultures were incubated with the Palmitoil-SEQ ID NO: 16-NH 2 peptide a a concentration of 10 ⁇ for 60 minutes before the application of capsaicin.
  • the amount of ⁇ -CGRP released was determined by an immunochemiluminescence assay. Values are shown as mean ⁇ standard deviation from the average (mean ⁇ sem), with n (number of neurons) ⁇ 25.
  • Figure 2 shows the inhibition by the Palmitoil-SEQ ID NO: 16-NH 2 peptide of capsaicin-induced nerve activity in rat knee nociceptor fibers,
  • (ad) Instantaneous frequency of nerve impulse produced by intra-arterial administration of 100 ⁇ of capsaicin 10 ⁇
  • Figure 3 shows the inhibition by the Palmitoil-SEQ ID NO: 16-NH 2 peptide of thermal hyperalgesia and scratching behavior in response to the itching caused by bile duct ligation.
  • the function of the TRPV1, TRPM8 and TRPA1 receptors can be modulated by peptides designed from the sequences of the TRPV1, TRPM8 and TRPA1 proteins, respectively.
  • the inventors have determined that peptides whose sequence derives from the TRPV1 sequence are capable of blocking the TRPV1 receptor channel, peptides whose sequence derives from the TRPM8 sequence are capable of blocking the TRPM8 receptor channel and peptides whose sequence derives from the TRPA1 sequence are capable of blocking the TRPA1 receptor channel.
  • treatment means the administration of a peptide according to the invention to alleviate or eliminate a disease or disorder or reduce or eliminate one or more symptoms associated with said disease or disorder.
  • treatment also encompasses alleviating or eliminating the physiological sequelae of the disease or disorder.
  • prevention refers to the ability of a peptide of the invention to prevent, delay or hinder the onset or development of a disease or disorder before its appearance.
  • skin means the set of layers that comprise it from the most superficial layer or stratum corneum to the deepest layer or hypodermis, both included. These layers are composed of different types of cells such as keratinocytes, fibroblasts, melanocytes and / or adipocytes among others.
  • the term “skin” includes the scalp.
  • skin, mucous and / or nail care comprises the prevention of diseases and / or disorders of the skin, mucous membranes and / or nails.
  • non-cyclic aliphatic group is used in the present invention to encompass linear or branched alkyl, alkenyl and alkynyl groups.
  • alkyl group refers to a saturated, linear or branched group, having between 1 and 24, preferably between 1 and 16, more preferably between 1 and 14, even more preferably between 1 and 12, still more preferably 1, 2, 3, 4, 5 or 6 carbon atoms and that is attached to the rest of the molecule through a single bond, including, for example and without limitation, methyl, ethyl, isopropyl, isobutyl, irec-butyl, heptyl, octyl , decyl, dodecyl, lauryl, hexadecyl, octadecyl, amyl, 2-ethylhexyl, 2-methylbutyl, 5-methylhexyl and the like.
  • alkynyl group refers to a group, linear or branched, having between 2 and 24, preferably between 2 and 16, more preferably between 2 and 14, even more preferably between 2 and 12, still more preferably 2, 3, 4, 5 or 6 carbon atoms with one or more carbon-carbon triple bonds, preferably 1, 2 or 3 carbon-carbon triple bonds, conjugated or unconjugated, which is bound to the rest of the molecule by a single bond, including, for example and without limitation, the ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, pentinyl group, such as 1 -pentinyl, and the like.
  • the alkynyl groups may also contain one or more carbon-carbon double bonds, including, for example and without limitation, the but-1-en-3-inyl, pent-4-en-1-ynyl group and the like.
  • alicyclyl group is used in the present invention to encompass, for example and without limitation, cycloalkyl or cycloalkenyl or cycloalkynyl groups.
  • cycloalkyl refers to a saturated mono- or polycyclic aliphatic group having between 3 and 24, preferably between 3 and 16, more preferably between 3 and 14, even more preferably between 3 and 12, still more preferably 3, 4 , 5 or 6 carbon atoms and which is attached to the rest of the molecule by a single bond, including, for example and without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methyl cyclohexyl, dimethyl cyclohexyl, octahydroindene, decahydronaphthalene, dodecahydrofenalene and the like.
  • cycloalkenyl refers to a non-aromatic mono- or polycyclic aliphatic group having between 5 and 24, preferably between 5 and 16, more preferably between 5 and 14, even more preferably between 5 and 12, still more preferably 5 or 6 carbon atoms, with one or more carbon-carbon double bonds, preferably 1, 2 6 3 carbon-carbon double bonds, conjugated or unconjugated, and which is attached to the rest of the molecule by a single bond, including, for example and without limiting sense, the cyclopent-1-in-1-yl group and the like.
  • cycloalkynyl refers to a non-aromatic mono- or polycyclic aliphatic group having between 8 and 24, preferably between 8 and 16, more preferably between 8 and 14, even more preferably between 8 and 12, still more preferably 8 or 9 carbon atoms, with one or more carbon-carbon triple bonds, preferably 1, 2 6 3 carbon-carbon triple bonds, conjugated or unconjugated, and which is attached to the rest of the molecule by a single bond, including, for example and without limitation, the cyclooct-2-in-1-yl group and the like.
  • the cycloalkynyl groups may also contain one or more carbon-carbon double bonds, including, for example and without limitation, the cyclooct-4-en-2-inyl group and the like.
  • aryl group refers to an aromatic group having between 6 and 30, preferably between 6 and 18, more preferably between 6 and 10, even more preferably 6 or 10 carbon atoms, comprising 1, 2, 3 or 4 aromatic rings, linked by a carbon-carbon bond or condensate, including, for example and without limitation, phenyl, naphthyl, diphenyl, indenyl, phenanthryl or anthranyl among others; or to an aralkyl group.
  • aralkyl group refers to an alkyl group substituted with an aromatic group, having between 7 and 24 carbon atoms and including, for example and without limitation, - (CH 2 ) i-6-phenyl, - (CH 2 ) i-6- (1-naphthyl), - (CH 2 ) i-6- (2-naphthyl), - (CH 2 ) i-6-CH (phenyl) 2 and the like.
  • heterocyclyl group refers to a 3-10 membered hydrocarbon ring, in which one or more of the ring atoms, preferably 1, 2 or 3 of the ring atoms, is a non-carbon element, such as for example nitrogen, oxygen or sulfur and which can be saturated or unsaturated.
  • the heterocycle may be a monocyclic, bicyclic or tricyclic cyclic system, which may include condensed ring systems; and the nitrogen, carbon or sulfur atoms may optionally be oxidized in the heterocyclyl radical; the nitrogen atom may be optionally quaternized; and the heterocyclyl radical may be partially or completely saturated or aromatic.
  • heterocyclic refers to a 5 or 6 membered ring.
  • saturated heterocyclyl groups are dioxane, piperidine, piperazine, pyrrolidine, morpholine and thiomorpholine.
  • aromatic heterocyclyl groups also known as heteroaromatic groups are pyridine, pyrrole, furan, thiophene, benzofuran, imidazoline, quinolein, quinoline, pyridine.
  • heteroarylalkyl group refers to an alkyl group substituted with a substituted or unsubstituted aromatic heterocyclyl group, the alkyl group having 1 to 6 carbon atoms and the aromatic heterocyclyl group having 2 to 24 carbon atoms and 1 to 3 atoms other than carbon and including, for example and without limitation, - (CH 2 ) 1-6 -imidazolyl, - (CH 2 ) 1-6 -triazolyl, - (CH 2 ) 1-6 -thienyl, - ( CH 2 ) 1-6 -furyl, - (CH 2 ) 1-6 -pyrrolidinyl and the like.
  • substitution may exist in the groups of the present invention where explicitly so indicated.
  • References in this document to substituted groups in the groups herein The invention indicates that the specified radical may be substituted in one or more positions available with one or more substituents, preferably in 1, 2 or 3 positions, more preferably in 1 or 2 positions, still more preferably in 1 position.
  • substituents include, for example and without limitation, CrC 4 alkyl; hydroxyl; CrC 4 alkoxy; Not me; CrC 4 aminoalkyl; CrC 4 carbonyloxy; CrC 4 oxycarbonyl; halogen such as fluorine, chlorine, bromine and iodine; cyano; nitro; azido; CC 4 alkylsulfonyl; thiol; CC 4 alkylthio; aryloxy such as phenoxy;
  • R b and R c are independently selected from the group consisting of H, alkyl AD 4, alkenyl C 2 -C 4 alkynyl , C 2 -C 4, C3-C10, aryl C6 Ci 8, C7-C17 aralkyl, 3-10-membered heterocyclyl or amino group protecting group.
  • the invention relates to a peptide, hereinafter peptide of the invention, selected from the group consisting of:
  • peptide comprising the sequence SEQ ID NO: 1 or a functionally equivalent variant, where the length of said peptide is equal to or less than 25 amino acids and where the asparagine of the sequence SEQ ID NO: 1 remains unchanged;
  • (I) peptide comprising the sequence SEQ ID NO: 2 or a functionally equivalent variant, wherein the length of said peptide is equal to or less than 25 amino acids;
  • peptide comprising the sequence SEQ ID NO: 3 or a functionally equivalent variant, where the length of said peptide is equal to or less than 25 amino acids, the arginine and glutamine of SEQ ID NO: 3 remain unchanged and where the peptide is not the sequence peptide SEQ ID NO: 4;
  • (V) peptide comprising the sequence SEQ ID NO: 5 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the peptide is not the sequence peptide SEQ ID NO: 6;
  • peptide comprising the sequence SEQ ID NO: 7 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the asparagine of SEQ ID NO: 7 closest to the C-terminal remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 8 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the valine and / or tryptophan of SEQ ID NO: 8 is they remain unchanged;
  • peptide comprising the sequence SEQ ID NO: 9 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the isoleucine of SEQ ID NO: 9 remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 10 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the amino acid of the V-terminal / end of SEQ ID NO: 10 it can only be isoleucine or leucine, and the valine of said sequence remains unchanged;
  • (ix) peptide comprising the sequence SEQ ID NO: 1 1 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the histidine of SEQ ID NO: 1 1 remains unchanged;
  • (x) peptide comprising the sequence SEQ ID NO: 12 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the peptide is not the sequence peptide
  • amino-terminal (/ V-terminal) and carboxy-terminal (C-terminal) ends of the peptide sequences may be chemically modified.
  • the / V-terminal substituent is selected from the group consisting of H, a polymer derived from polyethylene glycol and R-CO-, where R is selected from the group consisting of C1-C24 alkyl radical substituted or not substituted, substituted or unsubstituted C 2 -C 2 4 alkenyl, substituted or unsubstituted C 2 -C 24 alkynyl, substituted or unsubstituted C 3 -C 24 cycloalkyl, substituted or unsubstituted C 5 -C 24 cycloalkenyl, substituted C 8 -C 2 4 cycloalkenyl or unsubstituted, C 6 -C 3 aryl or substituted or unsubstituted, C7-C24 aralkyl substituted or not substituted, 3-10 heterocyclyl substituted or unsubstituted ring, and substituted or unsubstituted heteroarylalkyl of 2 to 24
  • the end / V-terminal substituent is selected from the group consisting of H, a polymer derived from polyethylene glycol of molecular weight between 200 and 35,000 Daltons, acetyl, irec-butanoyl, prenyl, hexanoyl, 2-methylhexanoyl, cyclohexanecarboxyl, octanoyl, decanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, oleoyl and linoleoyl.
  • the / V-terminal substituent is H, acetyl, lauroyl, myristoyl or palmitoyl.
  • Ri is acetyl or palmitoyl.
  • the C-terminal substituent is selected from the group consisting of -NR ⁇ , -ORi, -SRi, where Ri and R 2 are independently selected from the group consisting of H, a polymer derived from polyethylene glycol, C1-C24 substituted or unsubstituted alkyl, alkenyl C 2 -C 4 February substituted or unsubstituted alkynyl , C 2 -C 4 February substituted or unsubstituted cycloalkyl , C 3 -C 24 substituted or unsubstituted, cycloalkenyl C 5 -C 24 substituted or unsubstituted, C 8 -C 24 substituted or unsubstituted cycloalkynyl, C 6 -C 3 or substituted or unsubstituted aryl, C 7 -C 24 substituted or unsubstituted aralkyl, 3-10 substituted or unsubstituted 3-10 ring heterocycl
  • R1 and R2 may be joined by a carbon-carbon, saturated or unsaturated, forming a cycle with the nitrogen atom bond.
  • the substituent of the C-terminal end is -NR-
  • R 1 and R 2 are selected from the group consisting of H, a polymer derived from polyethylene glycol of molecular weight between 200 and 35,000 Daltons, methyl, ethyl, hexyl, dodecyl and hexadecyl.
  • R1 is H and R 2 is selected from the group consisting of H, methyl, ethyl, hexyl, dodecyl and hexadecyl.
  • the C-terminal substituent is selected from -OH and -NH 2 .
  • the peptide of SEQ ID NO: 6 (YGWTIGQNCRQWG) is described in WO 01/31019 A2.
  • the peptide of SEQ ID NO: 13 (DVIKALRLAMQL) is described in US 2008/0226664 A1.
  • the peptides of the invention comprise a sequence that is derived from a region of the TRP receptors and, preferably, are selected from the group of sequences schematized in Table 1, in which their sequence identifier is detailed:
  • the peptide of the invention is selected from the group of sequences described in Table 2, which comprise the sequences SEQ ID NO: 1-3, SEQ ID NO: 5 and SEQ ID NO: 7-12 described above. They are shown together with the sequence identifier and its function (TRP receptor they inhibit).
  • the peptides of the invention or their functionally equivalent variants have the ability to inhibit the TRPV1, TRPM8 and / or TRPA1 receptors.
  • He corresponding TRP receptor refers to a mammalian derived receptor, such as human, monkey, rat, mouse, dog, bovine species, rabbit and the like, of birds, fish or other animal .
  • the amino acid sequence of TRPV1 is registered in the GenBank database under accession number CAB89866 (Homo sapiens), that of TRPM8 under accession number ACQ66098 (Homo sapiens) and that of TRPA1 under accession number AC022867 ⁇ Homo sapiens).
  • the term "functionally equivalent variant”, as used in the present invention, means all those peptides derived from the sequence of the peptides of the invention by modification, insertion and / or elimination of one or more amino acids, provided and when the function of said peptide is maintained at least 20%, at least 50%, at least 80%, with respect to the function of the corresponding peptide of the invention without modifications, insertions and / or deletions.
  • the function of the peptide of the invention and its functionally equivalent variants is determined by measuring its inhibitory capacity of the activity of the TRP receptors, specifically by measuring the inhibition of calcium flow through the receptor.
  • Suitable methods for determining the ability of the functionally equivalent peptide or variant to inhibit TRP activity are known to the person skilled in the art and include, for example and without limitation, the method described in the examples of the present invention for the TRPV1 receptor, based on monitoring intracellular Ca 2+ signals in neuroblastoma cells expressing TRPV1 (SH-SY5Y-TRPV1).
  • Activation of the TRPV1 receptor by treatment with capsaicin involves the opening of the ionic channel of the receptor expressed in said cells and the consequent increase in the concentration of intracellular calcium.
  • the intracellular calcium concentration decreases with respect to the cells untreated with the inhibitor peptide or a functionally equivalent variant.
  • thermoreceptors for example and without limitation, the measurement of the capacity of inhibition of TRPM8 by the peptides of the invention in HEK293 cells expressing TRPM8 and whose receptors are activated by treatment with menthol is described, and the measurement of the inhibition of TRPA1 by the peptides of the invention in CHO cells expressing TRPA1 and whose receptors are activated by treatment with cinnamaldehyde.
  • a peptide of the invention or a functionally equivalent variant it is considered to inhibit the activity of TRPV1, TRPM8 and / or TRPA1 if it inhibits its function, that is, if the activity of TRPV1, TRPM8 and / or TRPA1 is decreased by at least 15%, at least 20%, at least one 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%, with respect to that of cells expressing the untreated TRP receptor with the inhibitor peptide.
  • Variants suitable for use in the present invention include those showing at least 25%, at least 40%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at at least 96%, at least 97%, at least 98% or at least 99% sequence identity with respect to the peptide sequence indicated above.
  • the degree of identity between two amino acid sequences can be determined by conventional methods, for example, by standard sequence alignment algorithms known in the state of the art, such as, for example, BLAST (AltschuI SF et al. Basic Local Alignment Search Tool J Mol Biol. 1990 Oct 5; 215 (3): 403-10).
  • the modification of the peptide of the invention to generate a functionally equivalent variant is carried out by substituting one or more amino acids of the peptide of the invention with one of its corresponding equivalent amino acids in terms of their properties.
  • the following amino acids are considered equivalent in their properties: glutamic acid (E) and aspartic acid (D); threonine (T) and serine (S); valine (V), leucine (L) and isoleucine (I); asparagine (N) and glutamine (Q); lysine (K), arginine (R) and histidine (H) and finally the aromatic amino acids phenylalanine (F), tryptophan (W) and tyrosine (Y) -
  • E glutamic acid
  • T threonine
  • S serine
  • valine V
  • leucine L
  • I isoleucine
  • I asparagine
  • N asparagine
  • glutamine Q
  • the peptides of the present invention and their functionally equivalent variants may exist as stereoisomers or mixtures of stereoisomers; for example, the amino acids that compose them can have an L-, D-, or be racemic configuration independently of each other. Therefore, it is possible to obtain isomeric mixtures as well as racemic or diastereomeric mixtures, or pure diastereomers or pure enantiomers, depending on the number of asymmetric carbons and what isomers or isomeric mixtures are present.
  • Preferred structures of the peptides of the invention and their functionally equivalent variants are pure isomers, that is, enantiomers or diastereomers.
  • cosmetically or pharmaceutically acceptable salts of the peptides provided by this invention.
  • the term "cosmetically or pharmaceutically acceptable salts” means a salt recognized for use in animals and more particularly in humans, and includes salts used to form base addition salts, whether inorganic, for example and without limitation, lithium, sodium, potassium, calcium, magnesium, manganese, copper, zinc or aluminum, among others, whether organic, for example and without limitation, ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, arginine, lysine, histidine or piperazine among others, or acid addition salts, whether organic, for example and without limitation, acetate, citrate, lactate, malonate, maleate, tartrate, fumarate, benzoate, aspartate, glutamate, succinate, oleate, trifluoroacetate, oxalate, pamoate or gluconate between others, or inorganic, such as for example and without limitation,
  • salt is not critical, as long as it is cosmetically or pharmaceutically acceptable.
  • Cosmetically or pharmaceutically acceptable salts of the peptides of the invention can be obtained by conventional methods, well known in the state of the art [Berge S.M. et al. (1977) J. Pharm. Sci. 66: 1-19].
  • Peptides can also be obtained by fermentation of a bacterial strain, modified or not by genetic engineering with the aim of producing the desired sequences, or by controlled hydrolysis of proteins of animal or vegetable origin, preferably vegetable, that release peptide fragments containing at least the desired sequence.
  • a method of obtaining the peptides of the invention and their functionally equivalent variants comprises the steps of:
  • the C-terminal end is attached to a solid support and the process is carried out in solid phase and, therefore, comprises the coupling of an amino acid with the protected / V-terminal end and the free C-terminal end on an amino acid. with the free / V-terminal end and the C-terminal end attached to a polymeric support; removal of the end / V-terminal protecting group; and repeating this sequence as many times as necessary to obtain the peptide of the desired length, finally followed by the cleavage of the synthesized peptide from the original polymeric support.
  • the functional groups of the amino acid side chains are conveniently maintained protected with temporary or permanent protecting groups throughout the synthesis, and can be simultaneously or orthogonally deprotected from the polymeric peptide cleavage process.
  • solid phase synthesis can be performed by a convergent strategy by coupling a peptide on the polymeric support or on a peptide or amino acid previously attached to the polymeric support.
  • Convergent synthesis strategies are widely known to experts in the field and are described in Lloyd-Williams P. et al. (1993) Tetrahedron 49: 1 1065-1 1 133.
  • the method may comprise the additional steps of deprotection of the / V-terminal and / or C-terminal ends and / or cleavage of the polymeric support peptide in the same order, using standard procedures and conditions known in the art, after which they can be modified the functional groups of said ends.
  • Optional modification of the / V-terminal and / or C-terminal ends can be performed with the peptide sequence of the peptide of the invention anchored to the polymeric support or once the peptide has been cleaved from the polymeric support.
  • protecting group refers to a group that blocks an organic functional group and that can be removed under controlled conditions.
  • the protecting groups, their relative reactivities and the conditions in which they remain inert are known to the person skilled in the art.
  • amides such as amide acetate, amide benzoate, amide pivalate
  • carbamates such as benzyloxycarbonyl (Cbz or Z), 2-chlorobenzyl (CIZ), para-nitrobenzyloxycarbonyl (pNZ), ⁇ erc-butyloxycarbonyl (Boc), 2,2,2-trichloroethyloxycarbonyl (Troc), 2- (trimethylsilyl) ethyloxycarbonyl ( Teoc), 9-fluorenylmethyloxycarbonyl (Fmoc) or allyloxycarbonyl (Alloc), trityl (Trt), methoxytrityl (Mtt), 2,4-dinitrophenyl (Dnp), / V- [1 - (4,4-dimethyl-2,6 -dioxocyclohex-1-iridene) ethyl (Dde), 1 - (4- (4,4-dimethyl-2,
  • Examples of representative protecting groups for the carboxyl group are esters, such as the butyl ester (tBu), allyl ester (All), triphenylmethyl ester (trityl ester, Trt), cyclohexyl ester (cHx), benzyl ester (Bzl), orio-nitrobenzyl ester, para-nitrobenzyl ester, para-methoxybenzyl ester, trimethylsilylethyl ester (TMS), 2-phenylisopropyl ester, fluorenylmethyl ester (Fm), 4- ( / V- [1 - (4,4-dimethyl-2,6-dioxcyclohexylidene) -3-methylbutyl] amino) benzyl (Dmab), among others; Preferred protecting groups of the invention are the esters of All, tBu, cHx, Bzl and Trt.
  • the side chains of the trifunctional amino acids can be protected during the synthetic process with temporary or
  • the arginine side chain is protected with a protective group selected from the group consisting of tosyl (Tos), 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr), Alloc, nitro, 2,2,4,6,7- pentamethyldihydrobenzofuran-5-sulfonyl (Pbf) and 2,2,5,7,8-pentamethylchroman-6-sulfonyl (Pmc),
  • the lysine side chain is protected with a protective group selected from the group consisting of CIZ, Z, 4- nitroZ, Fmoc, Boc, acetyl (Ac), Cough, Dde, ivDde, Dnp, Mtt and Alloc
  • the side chains of aspartic acid and glutamic acid are protected with a protective group selected from the group consisting of Trt, Bzl, cHx, tBu and All
  • the tyrosine side chain is protected with a protective group selected from
  • the invention relates to a cosmetic or pharmaceutical composition, hereinafter cosmetic or pharmaceutical composition of the invention, comprising at least one of the peptides of the invention or a functionally equivalent variant, its stereoisomers, mixtures thereof and / or its cosmetically or pharmaceutically acceptable salts, together with at least one cosmetic or pharmaceutically acceptable adjuvant.
  • the peptides of the present invention have a variable water solubility, depending on the nature of their sequence or the possible modifications in the / V-terminal and / or C-terminal ends that they present.
  • the peptides of the present invention can be incorporated into the compositions by aqueous solution, and those that are not soluble in water can be solubilized in solvents.
  • conventional cosmetics or pharmaceutically acceptable such as, for example and without limitation, ethanol, propanol, isopropanol, propylene glycol, glycerin, butylene glycol or polyethylene glycol or any combination thereof.
  • the cosmetic or pharmaceutically effective amount of the peptides of the invention to be administered, as well as their dosage, will depend on numerous factors, including the age, patient's condition, the nature or severity of the disorder or disease to be treated or prevented, the route and frequency of administration and the particular nature of the peptides to be used.
  • cosmetic or pharmaceutically effective amount is meant a non-toxic but sufficient amount of the peptide or peptides of the invention to provide the desired effect.
  • the peptides of the invention are used in the cosmetic or pharmaceutical composition of the present invention at cosmetic or pharmaceutically effective concentrations to achieve the desired effect; preferably, with respect to the total weight of the composition, between 0.00000001% (by weight) and 20% (by weight); preferably between 0.000001% (by weight) and 15% (by weight), more preferably between 0.00001% (by weight) and 10% (by weight) and even more preferably between 0.001% (by weight) and 5% (by weight).
  • peptides of the invention or their functionally equivalent variants, their stereoisomers, mixtures thereof and / or their cosmetically or pharmaceutically acceptable salts, can also be incorporated into vehiculization systems and / or cosmetic or pharmaceutical sustained release systems.
  • Such cosmetic or pharmaceutical vehicles may be liquids, such as water, oils or surfactants, including those of petroleum, animal, vegetable or synthetic origin, such as, for example and without limitation, peanut oil, soybean oil, mineral oil, sesame oil , castor oils, polysorbates, sorbitan esters, ether sulfates, sulfates, betaines, glycosides, maltósidos, fatty alcohols, nonoxinoles, poloxamers, polyoxyethylene, polyethylene glycols, dextrose, glycerol, digitonin and the like.
  • oils or surfactants including those of petroleum, animal, vegetable or synthetic origin, such as, for example and without limitation, peanut oil, soybean oil, mineral oil, sesame oil , castor oils, polysorbates, sorbitan esters, ether sulfates, sulfates, betaines, glycosides, maltósidos, fatty alcohols, nonoxinoles, poloxamers, polyoxyethylene, polyethylene glycol
  • sustained release is used in the conventional sense referring to a system of vehiculization of a compound that provides gradual release of said compound over a period of time and preferably, but not necessarily, with relatively constant levels of compound release over a period of time.
  • vehiculization or sustained-release systems include, without limitation, liposomes, mixed liposomes, oleosomes, niosomes, etosomes, miliparticles, microparticles, nanoparticles and solid lipid nanoparticles, nanostructured lipid supports, sponges, cyclodextrins, vesicles, micelles, mixed micelles of surfactants, mixed phospholipid-surfactant micelles, microspheres, microspheres and nanospheres, lipospheres, microcapsules, microcapsules and nanocapsules, as well as in microemulsions and nanoemulsions, which can be added to achieve greater penetration of the active ingredient and / or improve the pharmacokinetic properties and pharmacodynamics thereof.
  • Preferred vehiculization or sustained-release systems are liposomes, mixed micelles phospholipid tesioactive and microemulsions, more preferably water-in-oil microemulsions with internal reverse micelle structure.
  • Sustained release systems can be prepared by methods known in the state of the art, and the compositions containing them can be administered, for example, by topical or transdermal administration, including adhesive patches, non-adhesive patches, occlusive patches and microelectric patches, or by systemic administration, such as for example and without limitation by oral or parenteral route, including nasal, rectal, implantation or subcutaneous injection, or direct implantation or injection into a particular part of the body, and preferably should release a relatively quantity constant of the peptides of the invention.
  • the amount of peptide contained in the sustained release system will depend, for example, on the site of administration, the kinetics and duration of release of the peptide of the invention, as well as the nature of the disorder or disease to be treated or prevented.
  • the peptides of the present invention can also be adsorbed on solid organic polymers or solid mineral supports such as for example and without limitation talc, bentonite, silica, starch or maltodextrin among others.
  • compositions containing the peptides of the invention or their functionally equivalent variants, their stereoisomers, mixtures thereof and / or their cosmetically or pharmaceutically acceptable salts can also be incorporated into tissues, non-woven fabrics and products. toilets that are in contact directly with the skin, so that they release the peptides of the invention either by biodegradation of the tissue anchoring system, non-woven fabric or medical device or by their friction with the body, by body moisture, by the Skin pH or body temperature. Also, tissues and non-woven fabrics can be used to make garments that are in direct contact with the body.
  • Fabrics, non-woven fabrics, garments and sanitary products preferred are bandages, gauze, T-shirts, socks, socks, underwear, girdles, gloves, diapers, compresses, dressings, bedspreads, wipes, adhesive patches, non-adhesive patches, occlusive patches , microelectric patches and / or facial masks.
  • compositions containing the peptides of the invention or their functionally equivalent variants, their stereoisomers, mixtures thereof and / or their cosmetically or pharmaceutically acceptable salts can be used in different types of topically or transdermally applied compositions that will optionally include the cosmetically or pharmaceutically acceptable excipients necessary for the formulation of the desired administration form.
  • cosmetically or pharmaceutically acceptable excipients necessary for the formulation of the desired administration form.
  • One skilled in the art knows the different excipients that can be used in cosmetic or pharmaceutical compositions containing the peptides of the invention.
  • compositions of topical or transdermal application can be presented in any solid, liquid or semi-solid formulation, such as, for example and without limitation, creams, multiple emulsions such as, for example and without limitation, oil and / or silicone emulsions in water, emulsions of water in oil and / or silicone, emulsions of the water / oil / water or water / silicone / water type and emulsions of the oil / water / oil or silicone / water / silicone type, anhydrous compositions, aqueous dispersions, oils, milks, balms, foams, lotions, gels, cream gels, hydroalcoholic solutions, hydro-glycol solutions, hydrogels, liniments, serums, soaps, shampoos, conditioners, serums, polysaccharide films, ointments, mousses, ointments, powders, bars, pencils and vaporizers or aerosols ("sprays”), including permanence or "leave on" formulations
  • compositions of topical or transdermal application can be incorporated by means of techniques known to those skilled in the art to different types of solid accessories such as for example and without limitation bandages, gauze, T-shirts, socks, stockings, underwear, girdles, gloves , diapers, compresses, dressings, bedspreads, wipes, adhesive patches, non-adhesive patches, occlusive patches, microelectric patches or facial masks, or can be incorporated into different makeup line products such as makeup funds, such as fluid makeup funds and compact makeup funds, make-up lotions, cleansing milks, dark circles, eyeshadow, lipstick, lip balm, lip gloss and powder among others.
  • makeup funds such as fluid makeup funds and compact makeup funds, make-up lotions, cleansing milks, dark circles, eyeshadow, lipstick, lip balm, lip gloss and powder among others.
  • compositions of the invention may include agents that increase the percutaneous absorption of the peptides of the invention, such as and without limitation, dimethylsulfoxide, dimethylacetamide, dimethylformamide, surfactants, azone (1-dodecylazacycloheptan-2-one), alcohol , urea, ethoxyglycol, acetone, propylene glycol or polyethylene glycol among others.
  • agents that increase the percutaneous absorption of the peptides of the invention such as and without limitation, dimethylsulfoxide, dimethylacetamide, dimethylformamide, surfactants, azone (1-dodecylazacycloheptan-2-one), alcohol , urea, ethoxyglycol, acetone, propylene glycol or polyethylene glycol among others.
  • the cosmetic or pharmaceutical compositions object of the present invention can be applied in the local areas to be treated by iontophoresis, sonophoresis, electroporation, microelectric patches, mechanical pressure, osmotic pressure gradient, occlusive cure, microinjections or needleless injections by pressure, such as for example, oxygen pressure injections, or any combination thereof, to achieve greater penetration of the peptide of the invention.
  • the area of application will be determined by the nature of the disorder or disease to be treated or prevented.
  • cosmetic or pharmaceutical compositions containing the peptides of the invention or their functionally equivalent variants, their stereoisomers or their cosmetically or pharmaceutically acceptable salts can be used in different types of formulations for oral administration, preferably in the form of cosmetics or oral drugs, such as and without limitation in capsules, including gelatin capsules, soft capsules, hard capsules, tablets, including sugar-coated tablets, tablets, pills, powders, granulated forms, chewing gums, solutions, suspensions, emulsions, syrups, elixirs, polysaccharide films, jellies or jellies, as well as in any other presentation known to an expert in the field.
  • capsules including gelatin capsules, soft capsules, hard capsules, tablets, including sugar-coated tablets, tablets, pills, powders, granulated forms, chewing gums, solutions, suspensions, emulsions, syrups, elixirs, polysaccharide films, jellies or jellies, as well as in any other presentation known to
  • the peptides of the invention can be incorporated into any form of functional food or fortified food, such as and without limitation in dietary bars or in compact or non-compact powders. Said powders can be solubilized in water, soda, dairy products, soy derivatives or incorporated into dietary bars.
  • the peptides of the invention can be formulated with the usual excipients and adjuvants for oral compositions or food supplements, such as and without limitation, fatty components, aqueous components, humectants, preservatives, texturizing agents, flavors, aromas, antioxidants and common dyes in the food sector.
  • compositions containing the peptides of the invention or their functionally equivalent variants, their stereoisomers, mixtures thereof and / or their cosmetically or pharmaceutically acceptable salts can be administered in addition to topically or transdermally, by any other type of route. appropriate, for example orally or parenterally, for which they will include the pharmaceutically acceptable excipients necessary for the formulation of the desired administration form.
  • parenteral includes nasal, atrial, ophthalmic, rectal, urethral, vaginal, subcutaneous, intradermal, intravascular injections such as intravenous, intramuscular, intraocular, intravitreal, intracorneal, intraspinal, intramedullary, intracranial, intracervical, intracerebral, intrameningeal, intraarticular, intrahepatic, intrathoracic, intratracheal, intrathecal and intraperitoneal, as well as any other similar injection or infusion technique.
  • intravascular injections such as intravenous, intramuscular, intraocular, intravitreal, intracorneal, intraspinal, intramedullary, intracranial, intracervical, intracerebral, intrameningeal, intraarticular, intrahepatic, intrathoracic, intratracheal, intrathecal and intraperitoneal, as well as any other similar injection or infusion technique.
  • intravascular injections such as intravenous, intramuscular, intraocular, intravitreal
  • cosmetic or pharmaceutically acceptable adjuvants contained in the cosmetic or pharmaceutical compositions described in the present invention are the additional ingredients commonly used in cosmetic or pharmaceutical compositions, such as for example and without limitation, other anti-inflammatory and / or analgesic agents, other antipruritic agents, calming agents, anesthetic agents, inhibitors of aggregation of acetylcholine receptors, inhibitors of muscle contraction, anticholinergic agents, elastase inhibitors, matrix metalloprotease inhibitors, stimulating agents or inhibitors of the synthesis of melanin, bleaching or depigmenting agents, propigmentation agents, self-tanning agents, agents anti-aging agents, NO-synthase inhibitors, 5-reductase inhibitors, lysyl- and / or prolyl-hydroxylase inhibitors, antioxidant agents, free radical capture and / or atmospheric anti-pollution agents, carbonyl reactive species capture agents, agents antiglication, antihistamine agents, antiviral agents, antiparasitic agents,
  • additional ingredients should not unacceptably alter the benefits of the peptides of the present invention.
  • the nature of said additional ingredients may be synthetic or of natural origin, such as plant extracts, or come from a biotechnological process or a combination of a synthetic procedure and a biotechnological process. Additional examples can be found described in CTFA International Cosmetic Ingredient Dictionary & Handbook, 12th Edition (2008).
  • biotechnological method is understood as any procedure that produces the active substance, or part thereof, in an organism, or in a part thereof.
  • a further aspect of the present invention relates to a cosmetic or pharmaceutical composition
  • a cosmetic or pharmaceutical composition comprising a cosmetic or pharmaceutically effective amount of at least one peptide of the invention or a functionally equivalent variant, its stereoisomers, mixtures thereof and / or its cosmetic salts. or pharmaceutically acceptable, and also a cosmetic or pharmaceutically effective amount of at least one anti-wrinkle agent and / or anti-aging agent selected, without limitation, from the group formed by the extracts of Vitis vinifera, Rosa canina, Turmeric longa, Iris pallida, Theobroma cacao , Ginkgo biloba, Leontopodium alpinum or Dunaliella salina among others or at least one synthetic compound or product of biotechnological origin that is an agent wrinkle and / or antiaging agent such as and not limited Matrixyl ® [INCI: Palmitoyl Pentapeptide-4], Matrixyl 3000 ® [INCI: Palmitoyl Tetrapeptide-7, Palmitoy
  • a further aspect of the present invention relates to a cosmetic or pharmaceutical composition
  • a cosmetic or pharmaceutical composition comprising a cosmetic or pharmaceutically effective amount of at least one peptide of the invention or a functionally equivalent variant, its stereoisomers, mixtures thereof and / or its cosmetic salts. or pharmaceutically acceptable, and also a cosmetic or pharmaceutically effective amount of at least one natural extract or essential oil that is an anti-inflammatory and / or analgesic agent such as for example and without limitation, madecasoside, equinacin, amaranth seed oil, oil sandalwood, peach leaf extract, Aloe vera extracts, Arnica montana, Artemisia vulgaris, Asarum maximum, Calendula officinalis, Capsicum, CENTIPEDA CUNNINGHAMII, Chamomilla recutita, Crinum asiaticum, Hamamelis virginiana, procumbens Harpagophytum, Hypericum per ⁇ oratum, Lilium candidum, Malva sylvestri
  • a further aspect of the present invention relates to a cosmetic or pharmaceutical composition
  • a cosmetic or pharmaceutical composition comprising a cosmetic or pharmaceutically effective amount of at least one peptide of the invention or a functionally equivalent variant, its stereoisomers, mixtures thereof and / or its cosmetic salts. or pharmaceutically acceptable, and also a cosmetic or pharmaceutically effective amount of at least one natural extract or essential oil that is an antipruritic agent such as, for example and without limitation, extracts of Abelmoschus esculentus, Actaea alba, Aglaia odorata, Alkanna tinctoria, Althaea officinalis, Altingia excelsa, Andropogon virginicus, Aralia nudicaulis, Aralia racemosa, Mexican Argemone, Barleria prionitis, Camelia sinensis, Caesalpinia digyna, Campsis grandiflora, Carissa congesta, Carthamus oxyacantha, Cassia tora, Chrysant
  • the peptides of the invention or their functionally equivalent variants, their stereoisomers, mixtures thereof and / or their cosmetically or pharmaceutically acceptable salts, are capable of inhibiting the activity of the TRP receptors, preferably the TRPV1, TRPM8 and / or TRPA1 receptors.
  • the TRP receptor inhibitor peptides of the invention can be used for the treatment and / or prevention of disorders and / or diseases such as pain, inflammation, pruritus, diseases and / or respiratory disorders and / or diseases and / or disorders associated with calcium imbalances.
  • the invention relates to the use of at least one peptide selected from the group consisting of:
  • peptide comprising the SEO ID NO: 1 sequence or a functionally equivalent variant, where the length of said peptide is equal to or less than 25 amino acids and where the asparagine of the SEO ID NO: 1 sequence remains unchanged;
  • peptide comprising the SEO ID NO: 3 sequence or a functionally equivalent variant, where the length of said peptide is equal or less than 25 amino acids and where the arginine and glutamine of SEQ ID NO: 3 remain unchanged;
  • the invention relates to the use of at least one peptide selected from the group consisting of:
  • peptide comprising the sequence SEQ ID NO: 7 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the asparagine of SEQ ID NO: 7 closest to the C-terminal remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 8 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the valine and / or tryptophan of SEQ ID NO: 8 is they remain unchanged;
  • the invention relates to the use of at least one peptide selected from the group consisting of:
  • peptide comprising the sequence SEQ ID NO: 9 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the isoleucine of SEQ ID NO: 9 remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 10 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the amino acid of the V-terminal / end of SEQ ID NO: 10 it can only be isoleucine or leucine, and the valine of said sequence remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 1 1 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the histidine of SEQ ID NO: 1 1 remains unchanged;
  • the invention relates to the use of at least one peptide selected from the group consisting of:
  • peptide comprising the sequence SEQ ID NO: 1 or a functionally equivalent variant, where the length of said peptide is equal to or less than 25 amino acids and where the asparagine of the sequence
  • peptide comprising the sequence SEQ ID NO: 3 or a functionally equivalent variant, where the length of said peptide is equal to or less than 25 amino acids and where the arginine and glutamine of SEQ ID NO: 3 remain unchanged;
  • (v) peptide comprising the sequence SEQ ID NO: 7 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the asparagine of SEQ ID NO: 7 closest to the C-terminal remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 8 or a functionally equivalent variant, wherein the length of said peptide is equal or less than 20 amino acids, and where the valine and / or tryptophan of SEQ ID NO: 8 remain unchanged;
  • peptide comprising the sequence SEQ ID NO: 9 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the isoleucine of SEQ ID NO: 9 remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 10 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the amino acid of the V-terminal / end of SEQ ID NO: 10 it can only be isoleucine or leucine, and the valine of said sequence remains unchanged;
  • (ix) peptide comprising the sequence SEQ ID NO: 1 1 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the histidine of SEQ ID NO: 1 1 remains unchanged;
  • (x) peptide comprising the sequence SEQ ID NO: 12 or a functionally equivalent variant, wherein the length of said peptide is equal to or less than 20 amino acids;
  • the invention relates to the use of at least one peptide selected from the group consisting of:
  • peptide comprising the sequence SEQ ID NO: 1 or a functionally equivalent variant, where the length of said peptide is equal to or less than 25 amino acids and where the asparagine of the sequence SEQ ID NO: 1 remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 2 or a functionally equivalent variant, wherein the length of said peptide is equal to or less than 25 amino acids;
  • peptide comprising the sequence SEQ ID NO: 3 or a functionally equivalent variant, where the length of said peptide is equal to or less than 25 amino acids and where the arginine and glutamine of SEQ ID NO: 3 remain unchanged;
  • (v) peptide comprising the sequence SEQ ID NO: 7 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the asparagine of SEQ ID NO: 7 closest to the C-terminal remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 8 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the valine and / or tryptophan of SEQ ID NO: 8 is they remain unchanged;
  • peptide comprising the sequence SEQ ID NO: 9 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the isoleucine of SEQ ID NO: 9 remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 10 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the amino acid of the V-terminal / end of SEQ ID NO: 10 it can only be isoleucine or leucine, and the valine of said sequence remains unchanged;
  • (ix) peptide comprising the sequence SEQ ID NO: 1 1 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the histidine of SEQ ID NO: 1 1 remains unchanged;
  • (x) peptide comprising the sequence SEQ ID NO: 12 or a functionally equivalent variant, wherein the length of said peptide is equal to or less than 20 amino acids; its stereoisomers, mixtures thereof and / or their cosmetically or pharmaceutically acceptable salts, in the manufacture of a cosmetic or pharmaceutical composition for the treatment and / or care of the skin, mucous membranes and / or nails.
  • the invention relates to the use of at least one peptide selected from the group consisting of:
  • peptide comprising the sequence SEQ ID NO: 5 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the peptide is not the sequence peptide SEQ ID NO: 6;
  • peptide comprising the sequence SEQ ID NO: 7 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the asparagine of SEQ ID NO: 7 closest to the C-terminal remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 8 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the valine and / or tryptophan of SEQ ID NO: 8 is they remain unchanged;
  • the invention relates to a peptide selected from the group consisting of:
  • peptide comprising the sequence SEQ ID NO: 1 or a functionally equivalent variant, where the length of said peptide is equal to or less than 25 amino acids and where the asparagine of the sequence SEQ ID NO: 1 remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 3 or a functionally equivalent variant, wherein the length of said peptide is equal to or less than 25 amino acids, the arginine and glutamine of SEQ ID NO: 3 is they remain unchanged and where the peptide is not the sequence peptide SEQ ID NO: 4;
  • (v) peptide comprising the sequence SEQ ID NO: 7 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the asparagine of SEQ ID NO: 7 closest to the C-terminal remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 8 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the valine and / or tryptophan of SEQ ID NO: 8 is they remain unchanged;
  • peptide comprising the sequence SEQ ID NO: 9 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the isoleucine of SEQ ID NO: 9 remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 10 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the amino acid of the V-terminal / end of SEQ ID NO: 10 it can only be isoleucine or leucine, and the valine of said sequence remains unchanged;
  • (ix) peptide comprising the sequence SEQ ID NO: 1 1 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the histidine of SEQ ID NO: 1 1 remains unchanged;
  • (x) peptide comprising the sequence SEQ ID NO: 12 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the peptide is not the sequence peptide
  • the invention relates to a peptide selected from the group consisting of:
  • peptide comprising the sequence SEQ ID NO: 1 or a functionally equivalent variant, where the length of said peptide is equal to or less than 25 amino acids and where the asparagine of the sequence
  • peptide comprising the sequence SEQ ID NO: 3 or a functionally equivalent variant, where the length of said peptide is equal to or less than 25 amino acids and where the arginine and glutamine of SEQ ID NO: 3 remain unchanged;
  • (v) peptide comprising the sequence SEQ ID NO: 7 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the asparagine of SEQ ID NO: 7 closest to the C-terminal remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 8 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the valine and / or tryptophan of SEQ ID NO: 8 is they remain unchanged;
  • peptide comprising the sequence SEQ ID NO: 9 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the isoleucine of SEQ ID NO: 9 remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 10 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the amino acid of the V-terminal / end of SEQ ID NO: 10 it can only be isoleucine or leucine, and the valine of said sequence remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 1 1 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the histidine of SEQ ID NO: 1 1 remains unchanged;
  • (x) peptide comprising the sequence SEQ ID NO: 12 or a functionally equivalent variant, wherein the length of said peptide is equal to or less than 20 amino acids;
  • the invention relates to a peptide selected from the group consisting of:
  • peptide comprising the sequence SEQ ID NO: 1 or a functionally equivalent variant, where the length of said peptide is equal to or less than 25 amino acids and where the asparagine of the sequence SEQ ID NO: 1 remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 3 or a functionally equivalent variant, where the length of said peptide is equal to or less than 25 amino acids and where the arginine and glutamine of SEQ ID NO: 3 remain unchanged;
  • peptide comprising the sequence SEQ ID NO: 7 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the asparagine of SEQ ID NO: 7 closest to the C-terminal remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 8 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the valine and / or tryptophan of SEQ ID NO: 8 is they remain unchanged;
  • peptide comprising the sequence SEQ ID NO: 9 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the isoleucine of SEQ ID NO: 9 remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 10 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the amino acid of the V-terminal / end of SEQ ID NO: 10 it can only be isoleucine or leucine, and the valine of said sequence remains unchanged;
  • (ix) peptide comprising the sequence SEQ ID NO: 1 1 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the histidine of SEQ ID NO: 1 1 remains unchanged;
  • (x) peptide comprising the sequence SEQ ID NO: 12 or a functionally equivalent variant, wherein the length of said peptide is equal to or less than 20 amino acids;
  • the invention relates to a peptide selected from the group consisting of:
  • peptide comprising the sequence SEQ ID NO: 1 or a functionally equivalent variant, where the length of said peptide is equal to or less than 25 amino acids and where the asparagine of the sequence SEQ ID NO: 1 remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 2 or a functionally equivalent variant, wherein the length of said peptide is equal to or less than 25 amino acids;
  • peptide comprising the sequence SEQ ID NO: 3 or a functionally equivalent variant, where the length of said peptide is equal to or less than 25 amino acids and where the arginine and glutamine of SEQ ID NO: 3 remain unchanged;
  • the invention relates to a peptide selected from the group consisting of:
  • peptide comprising the sequence SEQ ID NO: 7 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the asparagine of SEQ ID NO: 7 closest to the C-terminal remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 8 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the valine and / or tryptophan of SEQ ID NO: 8 is they remain unchanged;
  • the invention relates to a peptide selected from the group consisting of:
  • peptide comprising the sequence SEQ ID NO: 9 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the isoleucine of SEQ ID NO: 9 remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 10 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the amino acid of the V-terminal / end of SEQ ID NO: 10 it can only be isoleucine or leucine, and the valine of said sequence remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 1 1 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the histidine of SEQ ID NO: 1 1 remains unchanged;
  • the invention relates to at least one peptide selected from the group consisting of:
  • peptide comprising the sequence SEQ ID NO: 5 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the peptide is not the sequence peptide SEQ ID NO: 6;
  • peptide comprising the sequence SEQ ID NO: 7 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the asparagine of SEQ ID NO: 7 closest to the C-terminal remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 8 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the valine and / or tryptophan of SEQ ID NO: 8 is they remain unchanged;
  • the invention relates to a method of inhibiting the TRPV1 receptor comprising the administration of a cosmetic or pharmaceutically effective amount of at least one peptide, selected from the group consisting of:
  • peptide comprising the sequence SEQ ID NO: 1 or a functionally equivalent variant, wherein the length of said peptide is equal or less than 25 amino acids and where the asparagine of the sequence SEQ ID NO: 1 remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 3 or a functionally equivalent variant, where the length of said peptide is equal to or less than 25 amino acids and where the arginine and glutamine of SEQ ID NO: 3 remain unchanged;
  • the invention relates to a method of inhibiting the TRPM8 receptor comprising the administration of a cosmetic or pharmaceutically effective amount of at least one peptide, selected from the group consisting of:
  • peptide comprising the sequence SEQ ID NO: 7 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the asparagine of SEQ ID NO: 7 closest to the C-terminal remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 8 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the valine and / or tryptophan of the
  • the invention relates to a method of inhibiting the TRPA1 receptor comprising the administration of a cosmetic or pharmaceutically effective amount of at least one peptide, selected from the group consisting of: (i) peptide comprising the sequence SEQ ID NO: 9 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the isoleucine of SEQ ID NO: 9 remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 10 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the amino acid of the V-terminal / end of SEQ ID NO: 10 it can only be isoleucine or leucine, and the valine of said sequence remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 1 1 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the histidine of SEQ ID NO: 1 1 remains unchanged;
  • the invention relates to a method for the treatment and / or prevention of pain, inflammation, pruritus, diseases and / or disorders of the respiratory tract and / or diseases and / or disorders associated with calcium imbalances comprising the administration of a cosmetically or pharmaceutically effective amount of at least one peptide, selected from the group consisting of:
  • peptide comprising the sequence SEQ ID NO: 1 or a functionally equivalent variant, where the length of said peptide is equal to or less than 25 amino acids and where the asparagine of the sequence SEQ ID NO: 1 remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 3 or a functionally equivalent variant, wherein the length of said peptide is equal or less than 25 amino acids and where the arginine and glutamine of SEQ ID NO: 3 remain unchanged;
  • (v) peptide comprising the sequence SEQ ID NO: 7 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the asparagine of SEQ ID NO: 7 closest to the C-terminal remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 8 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the valine and / or tryptophan of SEQ ID NO: 8 is they remain unchanged;
  • peptide comprising the sequence SEQ ID NO: 9 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the isoleucine of SEQ ID NO: 9 remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 10 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the amino acid of the V-terminal / end of SEQ ID NO: 10 it can only be isoleucine or leucine, and the valine of said sequence remains unchanged;
  • (ix) peptide comprising the sequence SEQ ID NO: 1 1 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the histidine of SEQ ID NO: 1 1 remains unchanged;
  • (x) peptide comprising the sequence SEQ ID NO: 12 or a functionally equivalent variant, wherein the length of said peptide is equal to or less than 20 amino acids;
  • the invention relates to a method for the treatment and / or care of skin, mucous membranes and / or nails comprising the administration of a cosmetic or pharmaceutically effective amount of at least one peptide, selected from the group consisting of:
  • peptide comprising the sequence SEQ ID NO: 1 or a functionally equivalent variant, where the length of said peptide is equal to or less than 25 amino acids and where the asparagine of the sequence SEQ ID NO: 1 remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 3 or a functionally equivalent variant, where the length of said peptide is equal to or less than 25 amino acids and where the arginine and glutamine of SEQ ID NO: 3 remain unchanged;
  • (v) peptide comprising the sequence SEQ ID NO: 7 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the asparagine of SEQ ID NO: 7 closest to the C-terminal remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 8 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the valine and / or tryptophan of the
  • peptide comprising the sequence SEQ ID NO: 9 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the isoleucine of SEQ ID NO: 9 remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 10 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the amino acid of the / V-terminal end of SEQ ID NO: 10 can only be isoleucine or leucine, and the valine of said sequence remains unchanged;
  • (ix) peptide comprising the sequence SEQ ID NO: 1 1 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the histidine of SEQ ID NO: 1 1 remains unchanged;
  • (x) peptide comprising the sequence SEQ ID NO: 12 or a functionally equivalent variant, wherein the length of said peptide is equal to or less than 20 amino acids;
  • the invention relates to a method of cancer treatment, which comprises the administration of a therapeutically effective amount of at least one peptide selected from the group consisting of:
  • peptide comprising the sequence SEQ ID NO: 7 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the asparagine of SEQ ID NO: 7 closest to the C-terminal remains unchanged;
  • peptide comprising the sequence SEQ ID NO: 8 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the valine and / or tryptophan of SEQ ID NO: 8 is they remain unchanged;
  • the cancer is prostate cancer and / or pancreatic cancer.
  • the amino-terminal (/ V-terminal) and carboxy-terminal (C-terminal) ends of the above peptide sequences may be chemically modified.
  • the / V-terminal substituent is selected from the group consisting of H, a polymer derived from polyethylene glycol and R-CO-, where R is selected from the group consisting of C1-C24 alkyl radical substituted or not substituted, substituted or unsubstituted C 2 -C 2 4 alkenyl, substituted or unsubstituted C 2 -C 24 alkynyl, substituted or unsubstituted C 3 -C 24 cycloalkyl, substituted or unsubstituted C 5 -C 24 cycloalkenyl, substituted C 8 -C 2 4 cycloalkenyl or unsubstituted, C 6 -C 3 or substituted or unsubstituted aryl, substituted or unsubstituted C
  • the end / V-terminal substituent is selected from the group consisting of H, a polymer derived from polyethylene glycol of molecular weight between 200 and 35,000 Daltons, acetyl, irec-butanoyl, prenyl, hexanoyl, 2-methylhexanoyl, cyclohexanecarboxyl, octanoyl, decanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, oleoyl and linoleoyl.
  • the / V-terminal substituent is H, acetyl, lauroyl, myristoyl or palmitoyl.
  • R1 is acetyl or palmitoyl.
  • the C-terminal substituent is selected from the group consisting of -NR ⁇ , -OR1, -SR1, where R1 and R 2 are independently selected from the group consisting of H, a polymer derived from polyethylene glycol, C1-C24 substituted or unsubstituted alkyl, alkenyl C 2 -C 4 February substituted or unsubstituted alkynyl , C 2 -C 4 February substituted or unsubstituted, C3-C24 substituted or unsubstituted cycloalkyl , C5-C24 substituted or unsubstituted , substituted or unsubstituted C 8 -C 2 4 cycloalkynyl, C 6 -C 3 or substituted or unsubstituted aryl, substituted or unsubstituted C 7 -C 24 aralkyl, substituted or unsubstituted 3-10 ring heterocyclyl, and substituted heteroarylal
  • R1 and R2 may be joined by a carbon-carbon, saturated or unsaturated, forming a cycle with the nitrogen atom bond. More preferably the substituent of the C-terminal end is -NR-
  • R1 is H and R 2 is selected from the group consisting of H, methyl, ethyl, hexyl, dodecyl and hexadecyl
  • the C-terminal substituent is selected from -OH and -NH 2 .
  • the peptides of the invention or their functionally equivalent variants, their stereoisomers, mixtures thereof and / or their cosmetically or pharmaceutically acceptable salts are used for the treatment and / or prevention of pain, inflammation and / or pruritus. that are a consequence or concur with epithelial, gastrointestinal diseases or disorders of the cardiovascular system, urinary tract, endocrine system, brain, reproductive system, respiratory tract and / or cancer.
  • the pain is selected, for example and without limitation, from the group consisting of acute pain, chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, visceral pain, abdominal pain, digestive system pain, system pain respiratory, urogenital system pain, endocrine system pain, heart pain, pancreatic pain, liver pain, pain due to gallstones, cholestasis, intestinal pain, stomach pain, pain due to duodenal ulcer, pain due to esophagitis, pain due at gastroesophageal reflux, spleen pain, blood vessel pain, pain due to thalamic syndrome, irritable bowel syndrome, pain associated with Crohn's disease, diverticulitis, gastrointestinal mucositis, headache, tension headache, headache associated with sinusitis, migraine, eye pain, dry eye syndrome, post-operative pain, post-operative pain due to incisions s surgery, post-operative pain due to the insertion of bone implants, post-operative pain due to bone replacement, post-operative pain due to infections, post-operative
  • the inflammation is selected, for example and without limitation, from the group consisting of neurogenic inflammation, joint inflammation, tendon inflammation, muscle inflammation, sepsis, vascular inflammation, respiratory inflammation, chronic obstructive pulmonary disease, asthma, otitis, intestinal inflammation, pancreatitis, hepatitis, conditions related to chronic inflammation, with acute inflammation, nephritis, systemic lupus erythematosus, inflammatory bowel disease, Crohn's disease, rheumatoid arthritis, osteoarthritis, glomerulonephritis, neuritis, nervous tissue inflammation, multiple sclerosis, immune system disorders, Sjógren's syndrome, rhinitis, atherosclerosis, myocarditis, pericarditis, vasculitis, psoriasis, sensitive skin, dermatitis, atopic dermatitis, contact dermatitis, diaper dermatitis, eczema, rosacea, burns, sunburn,
  • the pruritus is selected from the itching associated with diseases and / or epithelial disorders, such as and without limitation, dermatitis, atopic dermatitis, photodermatosis, eczema, sensitive skin, psoriasis, dandruff, seborrhea, athlete's foot, sunburn, xerosis and dry skin, or pruritus associated with dialysis, pregnancy, menopause, acquired immunodeficiency virus infection, chicken pox, herpes, malignant neoplasms, Hodgkin's disease, leukemia, myeloma , lymphoma, solid tumors, lung cancer, liver diseases, jaundice, cholestasis, liver failure, cirrhosis, polycythemia, hypereosinophilic syndrome, essential thrombocythemia, myelodysplastic syndrome, iron deficiency anemia, systemic lupus erythematosus, en
  • respiratory diseases and / or disorders are selected, for example and without limitation, from the group consisting of obstructive diseases such as chronic obstructive pulmonary disease, emphysema, chronic bronchitis, asthma, asthma caused by industrial irritants, cystic fibrosis, bronchiectasis, bronchiolitis, allergic bronchopulmonary aspergillosis, or tuberculosis; Restrictive pulmonary diseases such as asbestosis, radiation-caused fibrosis, extrinsic allergic alveolitis or insensitivity pneumonitis, childhood respiratory distress syndrome, idiopathic pulmonary fibrosis, sarcoidosis, idiopathic interstitial pneumonia, eosinophilic pneumonia, lymphangioleiomyomatosis, Langerhave alveolar and pulmonary cell histiocytosis pulmonary; respiratory tract infections including common cold, sinusitis, tonsillitis, pharyngitis, laryngitis or pneumonia;
  • the diseases and / or disorders associated with calcium imbalances are selected, for example and without limitation, from the group consisting of vitamin D deficiency, rickets, osteomalacia, growth retardation, osteoporosis, post-menopausal osteoporosis , hypercalciuria, hypocalciuria, hypercalcemia, hypocalcemia and disorders related to parathyroid hormone, among others.
  • gastrointestinal diseases and / or disorders are selected, for example and without limitation, from the group consisting of inflammatory bowel disease, intestinal colic, Crohn's disease, pancreatitis, hepatitis, gastroesophageal reflux disease, duodenal ulcer, esophagitis , colitis or ulcerative colitis, among others.
  • epithelial diseases and / or disorders are selected, for example and without limitation, from the group formed by touch sensitivity, cold sensitivity, heat sensitivity, skin irritation, post-depilation skin irritation, post skin irritation -have, dermatitis, atopic dermatitis, allergic contact dermatitis, diaper dermatitis, photodermatosis, psoriasis, eczema, rosacea, burns, sunburn, sensitive skin, xerosis or dry skin among others.
  • cardiovascular diseases and / or disorders are selected, for example and without limitation, from the group consisting of angina, ischemia, reperfusion, hypertension, chronic heart disease or cardiac fibrosis, among others.
  • brain diseases and / or disorders are selected, for example and without limitation, from the group consisting of cerebral infarction, cerebral ischemia, cognitive disorders, memory problems, schizophrenia, bipolar disorder, Alzheimer's disease (AD) , Parkinson's disease, Huntington's disease, neurodegeneration, stroke, post stroke pain, multiple sclerosis, amyotrophic lateral sclerosis (ALS), and other brain disorders caused by trauma or other insults including aging, among others.
  • diseases and / or disorders of the urinary tract are selected, for example and without limitation, from the group formed by urinary incontinence, overactive bladder syndrome, cystitis, urination disorders, pain associated with kidney stones and renal colic, among others.
  • diseases and / or disorders of the reproductive system are selected, for example and without limitation, from the group formed by vulvodynia, menstrual pain and vaginitis, among others.
  • the diseases and / or disorders associated with different types of cancer and / or their treatment are selected, for example and without limitation, from the group consisting of neoplasms of lymphoreticular origin, bone cancer, osteosarcoma, liposarcoma, cancer breast, neoplasms of lymphoreticular origin, bladder cancer, colon cancer, endometrial cancer, head and neck cancer, lung cancer, melanoma, ovarian cancer, prostate cancer, skin cancer and rectal cancer, among others .
  • Electrospray mass spectrometry analysis was carried out in a WATERS Alliance with a ZQ 2000 detector using a mixture of MeCN: H 2 0 4: 1 (+ 0.1% TFA) as mobile phase and a flow of 0 , 2 mL / min.
  • the aminoacyl resins obtained were washed with DMF (5 x 1 min), DCM (4 x 1 min), diethyl ether (4 x 1 min) and dried in vacuo.
  • Fmoc-L-Ser (tBu) -0-2-CITrt-® was washed and deprotected as described in the general methods for incorporating the following amino acids. On each of the two resins and following the described protocols, 0.22 g of Fmoc-L-Glu (OtBu) -OH, 0.31 g of Fmoc-L-Gln (Trt) -OH, 0, were sequentially coupled.
  • Fmoc-L-Ser (tBu) -AM-MBHA and Fmoc-L-Ser (tBu) -0-2-CITrt-® were washed and unprotected as described in general methods to incorporate the following amino acids.
  • Fmoc-L-Arg (Pbf) -AM-MBHA and Fmoc-L-Arg (Pbf) -0-2-CITrt-® were washed and unprotected as described in general methods to incorporate the following amino acids.
  • Fmoc-L-Glu (OtBu) -AM-MBHA and Fmoc-L-Glu (OtBu) -0-2-CITrt-® were washed and unprotected as described in general methods to incorporate the following amino acids.
  • Boc -L-Leu-L-Gln (Trt) -L-Arg (Pbf) -L-Ala-AM-MBHA and Fmoc-L-Met-Glv-L-Glu (OtBu) - -L-Thr (tBu ) -L-Val-L-Asn (mL-Lvs (Boc) -L-lle-L-Ala-L-Gln (T ⁇
  • Fmoc-L-Ala-AM-MBHA and Fmoc-L-Ala-O-2-CITrt-® were washed and deprotected as described in the general methods for incorporating The following amino acids.
  • Fmoc-L-Asn (Trt) -AM-MBHA and Fmoc-L-Asn (Trt) -0-2-CITrt-® were washed and unprotected as described in general methods to incorporate the following amino acids.
  • Fmoc-L-Arg (Pbf) -AM-MBHA and Fmoc-L-Arg (Pbf) -0-2-CITrt-® were washed and unprotected as described in general methods to incorporate the following amino acids.
  • Fmoc-L-Glu (OtBu) -AM-MBHA and Fmoc-L-Glu (OtBu) -0-2-CITrt-® were washed and unprotected as described in general methods to incorporate the following amino acids.
  • 0.16 g of Fmoc-L-Ala-OH, 0.18 g of Fmoc-L-lle-OH, 0.21 g of Fmoc-L were sequentially coupled.
  • the Fmoc / V-terminal group was deprotected from the peptidyl resins obtained in Examples 2 to 18 as described in the general methods (20% piperidine in DMF, 1 x 5 min followed by 1 x 20 min). Subsequently, the peptidyl resins were washed with DMF (5 x 1 min), DCM (4 x 1 min), diethyl ether (4 x 1 min) and dried in vacuo.
  • 0.05 mmol of the peptidyl resins obtained in Example 19 were treated with 28.6 ⁇ of acetic anhydride (0.5 mmol; 10 eq.) In the presence of 10 eq. of DIEA (87.1 ⁇ _; 0.5 mmol) using 0.5 mL of DMF as solvent. They were allowed to react for 30 min, after which the peptidyl resins were washed with DMF (5 x 1 min), DCM (4 x 1 min), diethyl ether (4 x 1 min) and dried in vacuo.
  • H- -MGETVN-NH 2 (SEQ ID NO: 1 -NH 2 ) 649.73 649.69
  • H- -NKIAQES-NH 2 (SEQ ID NO: 2-NH 2 ) 788.87 788.84
  • H- -IWKLQR-NH 2 (SEQ ID NO: 3-NH 2 ) 843.05 843.03
  • H- -MGETVNKIAQE-NH 2 (SEQ ID NO: 21 -NH 2 ) 1219.39 1219.36
  • H- -IAEVQK-NH 2 (SEQ ID NO: 10-NH 2 ) 686.82 686.79
  • H- -VQKHAS-NH 2 (SEQ ID NO: 1 1 -NH 2 ) 668.76 668.91
  • H- -VGDIAEVQKHAS-NH 2 (SEQ ID NO: 33-NH 2 ) 1253.38 1253.73
  • H- -RIAMQV-NH 2 (SEQ ID NO: 12-NH 2 ) 716.91 716.80
  • H- -MGETVN-OH (SEQ ID NO: 1) 650.72 650.67
  • H- -NKIAQES-OH (SEQ ID NO: 2) 789.86 789.98
  • H- -MGETVNKIAQESKNIWKLQRA-OH (SEQ ID NO: 17) 2445.82 2446.72 H-FGYTVG-OH (SEQ ID NO: 5) 643.71 643.68
  • H-TVQENN-OH (SEQ ID NO: 7) 703.72 703.70
  • H-NDQVWK-OH (SEQ ID NO: 8) 789.86 789.83
  • H-VGDIAE-OH (SEQ ID NO: 9) 603.64 603.53
  • H-IAEVQK-OH (SEQ ID NO: 10) 687.81 687.89
  • H-VQKHAS-OH (SEQ ID NO: 1 1) 669.75 670.39
  • H-VGDIAEVQKHAS-OH (SEQ ID NO: 33) 1254.37 1254.34
  • H-VGDIAEVQKHASLKRIAMQV-OH (SEQ ID NO: 34) 2194.18 2193.81
  • Palm-MGETVN-NH 2 (Palmitoil-SEQ ID NO: 1 -NH 2 ) 888.14 887.88
  • Palm-NKIAQES-NH 2 (Palmitoil-SEQ ID NO: 2-NH 2 ) 1027.28 1027.73
  • Palm-MGETVNKIAQES-NH 2 (Palmitoil-SEQ ID NO: 16-NH 2 ) 1544.87 1544.84
  • Palm-IWKLQR-NH 2 (Palmitoil-SEQ ID NO: 3-NH 2 ) 1081, 46 1081, 19
  • Palm-MGETVNKIAQE-NH 2 (Palmitoil-SEQ ID NO: 21 -NH 2 ) 1457.80 1457.43
  • Palm-MGETVNKIAQESKNIWKLQRA-NH 2 (Palmitoil-SEQ ID NO: 17-NH 2 ) 2683.24 2683.04
  • Palm-FGYTVG-NH 2 (Palmitoil-SEQ ID NO: 5-NH 2 ) 881, 13 881, 02
  • Palm-TVQENN-NH 2 (Palmitoil-SEQ ID NO: 7-NH 2 ) 941, 14 941, 1 1
  • Palm-FGYTVGTVQENN-NH 2 (Palmitoil-SEQ ID NO: 31 -NH 2 ) 1565.83 1565.63
  • Palm-NDQVWK-NH 2 (Palmitoil-SEQ ID NO: 8-NH 2 ) 1027.28 1027.24
  • Palm-FGYTVGTVQENNDQVWKFQR-NH 2 (Palmitoil-SEQ ID NO: 32-NH 2 ) 2655.03 2655.00
  • Palm-VGDIAE-NH 2 (Palmitoil-SEQ ID NO: 9-NH 2 ) 841, 06 840.69
  • Palm-IAEVQK-NH 2 (Palmitoil-SEQ ID NO: 10-NH 2 ) 925.23 925.21
  • Palm-VQKHAS-NH 2 (Palmitoil-SEQ ID NO: 1 1 -NH 2 ) 907.17 907.45
  • Palm-VGDIAEVQKHAS-NH 2 (Palmitoil-SEQ ID NO: 33-NH 2 ) 1491, 79 1491, 84
  • Palm-RIAMQV-NH 2 (Palmitoil-SEQ ID NO: 12-NH 2 ) 955.32 955.06
  • Palm-VGDIAEVQKHASLKRIAMQV-NH 2 (Palmitoil-SEQ ID NO: 34-NH 2 ) 2431, 60 2431, 61
  • Palm-MGETVN-OH (Palmitoil-SEQ ID NO: 1) 889.13 889.77
  • Palm-NKIAQES-OH (Palmitoil-SEQ ID NO: 2) 1028.27 1028.44
  • Palm-MGETVNKIAQES-OH (Palmitoil-SEQ ID NO: 16) 1545.86 1545.77
  • Palm-IWKLQR-OH (Palmitoil-SEQ ID NO: 3) 1082.45 1082.42
  • Palm-MGETVNKIAQE-OH (Palmitoil-SEQ ID NO: 21) 1458.79 1459.30
  • Palm-MGETVNKIAQESKNIWKLQRA-OH (Palmitoil-SEQ ID NO: 17) 2684.23 2683.63
  • Palm-FGYTVG-OH (Palmitoil-SEQ ID NO: 5) 882.12 882.30
  • Palm-TVQENN-OH (Palmitoil-SEQ ID NO: 7) 942.13 942.21 Palm-FGYTVGTVQENN-OH (Palmitoil-SEQ ID NO: 31) 1566.82 1566.55
  • Palm-NDQVWK-OH (Palmitoil-SEQ ID NO: 8) 1028.27 1028.75
  • Palm-FGYTVGTVQENNDQVWKFQR-OH (Palmitoil-SEQ ID NO: 32) 2656.02 2655.68
  • Palm-VGDIAE-OH (Palmitoil-SEQ ID NO: 9) 842.05 842.17 Palm-IAEVQK-OH (Palmitoil-SEQ ID NO: 10) 926.22 926.55
  • Palm-VQKHAS-OH (Palmitoil-SEQ ID NO: 1 1) 908.16 908.24
  • Palm-VGDIAEVQKHAS-OH (Palmitoil-SEQ ID NO: 33) 1492.78 1492.91
  • Palm-RIAMQV-OH (Palmitoil-SEQ ID NO: 12) 956.31 956.95
  • Palm-VGDIAEVQKHASLKRIAMQV-OH (Palmitoil-SEQ ID NO: 34) 2432.59 2432.25
  • SH-SY5Y neuroblastoma cells which express rat TRPV1 stably (SH-SY5Y-TRPV1), by monitoring Ca 2+ signals induced by capsaicin by microfluorography using a fluorescence plate reader.
  • SH-SY5Y-TRPV1 cells were cultured in Earle's minimum medium (MEM) containing 10% (v / v) fetal calf serum (FCS), supplemented with 1% non-essential amino acids, 2 mM L-glutamine, 100 ⁇ g mL streptomycin, 100 U / mL penicillin and 0.4 ⁇ g / mL puromycin.
  • MEM Earle's minimum medium
  • FCS fetal calf serum
  • the cells were grown in an incubator with a humid atmosphere at 37 ° C and 5% C0 2 .
  • the cells were dispersed by enzymatic methods and seeded in 96-well plates. Cells were incubated with the peptides at 10 ⁇ for 1 h and subsequently treated with 5 ⁇ Fluo-4 acetoxymethyl ester in the presence of 0.02% resuspended pluronic acid in Hank's balanced saline solution (HBSS: 140 mM NaCI, 4 mM KCI, 1 mM MgCI 2 , 1.8 mMCaCI 2 , 5 mM D-glucose, 10 mM HEPES, pH 7.4) for 40-50 min at 37 ° C, after which they were transferred to a plate reader fluorescence.
  • HBSS Hank's balanced saline solution
  • TRPV1 activation was performed with a pulse of 10 ⁇ of capsaicin with a microinjector for 10 s.
  • the Fluo-4 probe was excited at 500 nm and the emitted fluorescence was filtered with a 535 nm filter.
  • the measurements were normalized with respect to the activity of the receptor in the absence of peptides (vehicle, 0.1% DMSO).
  • the inhibitory activity of the peptides of the invention was evaluated in SH-SY5Y-TRPV1 cells by electrophysiology. Cultured cells were dispersed by enzymatic methods and seeded at low density in 33 mm diameter Petri dishes to perform electrophysiological recordings. Membrane currents and voltages were recorded by electrophysiological membrane clamping techniques using the total current recording configuration [Garc ⁇ a-Sanz N. et al. (2004) J. Neurosci. 24: 5307-5314; Valente P et al. (2008) FASEB J. 22: 3298-3309].
  • the pipette solution consisted of 150 mM NaCI, 3 mM MgCI 2 , 5 mM EGTA and 10 mM HEPES pH 7.2 adjusted with NaOH and the bath solution consisted of 150 mM NaCI, 6 mM CsCI, 1 mM MgCI 2 , 1.5 mM CaCI 2 , 10 mM D-glucose and 10 mM HEPES pH 7.4 adjusted with CsOH.
  • TRPV1 activation was performed with pulses of 10 ⁇ capsaicin for 10 s, using a manual gravity perfusion system.
  • the log pipettes were prepared from thin-walled borosilicate glass capillaries (World Precision Instruments, Sarasota, FL), stretched with a horizontal stretcher (P-97, Sutter Ins. Co., Novato, CA) until obtaining a 2-4 ⁇ resistance.
  • Data were recorded by filtering at 10 kHz (EPC10 amplifier and software from HEKA electronics, Lambrecht, Germany or Multiclamp amplifier, pClamp software and a 1322A Digidata digitizer from Molecular Devices, Palo Alto, California) and filtering at 3 kHz for analysis ( 8.54 PulseFit, HEKA; Origin 7.5, pClamp9, WinASCD software by G.
  • the pipette resistance was generally less than 10 ⁇ and to minimize the errors in the voltage it was compensated at 60-80%. All measurements were made at 20-21 ° C. The measurements were normalized with respect to receptor activity in the absence of peptides (vehicle, 0.1% DMSO).
  • Table 5 details the TRPV1 activity values for those peptides that showed TRPV1 activity inhibition values greater than 15%.
  • the most potent peptide was the Palmitoil-SEQ ID NO: 16-NH 2 peptide. which blocked the TRPV1 receiver by 80%.
  • HEK293-TRPM8 The inhibitory activity of the peptides of the invention in the human embryonic kidney cell line HEK293, which stably expresses the rat TRPM8 receptor (HEK293-TRPM8), was evaluated by monitoring Ca 2+ signals induced by menthol using a fluorescence plate reader.
  • HEK293-TRPM8 cells were cultured in modified Dulbecco Eagle (DMEM) medium, supplemented with 10% (v / v) FCS, 100 ⁇ g / mL streptomycin and 100 U / mL penicillin, and 0.2 mg / mL geneticin . The cells were grown in an incubator with a humid atmosphere at 37 ° C and 5% C0 2 .
  • DMEM modified Dulbecco Eagle
  • the cells were dispersed by enzymatic methods and seeded in 96-well plates.
  • the cells were incubated with the peptides at 10 ⁇ for 1 h and subsequently treated with 5 ⁇ Fluo-4 acetoxymethyl ester in the presence of 0.02% resuspended pluronic acid in Hank's balanced saline solution (HBSS: 140 mM NaCI, 4 mM KCI, 1 mM MgCI 2 , 1, 8 mMCaCI 2.5 mM D-glucose, 10 mM HEPES, pH 7.4) for 40-50 min at 37 ° C, after which they were transferred to a fluorescence plate reader.
  • HBSS Hank's balanced saline solution
  • TRPM8 activation was performed with a 100 ⁇ un pulse of menthol at 30 ° C with a microinjector for 10 s.
  • the Fluo-4 probe was excited at 500 nm and the emitted fluorescence was filtered with a 535 nm filter.
  • the ionic channel activity was calculated as the difference in fluorescence signal between the baseline (before the addition of menthol) and the fluorescent signal after the agonist was added.
  • the measurements were normalized with respect to receptor activity in the absence of peptides (vehicle, 0.1% DMSO).
  • the inhibitory activity of the peptides of the invention was evaluated in the HEK293-TRPM8 cells by electrophysiology, following the method described in Example 24 and using 100 ⁇ pulses of menthol at 30 ° C instead of capsaicin to activate the receptor TRPM8. Measurements of channel activity were normalized with respect to receptor activity in the absence of peptides (vehicle, 0.1% DMSO).
  • Table 6 details the TRPM8 activity values for those peptides that showed TRPM8 activity inhibition values greater than 15%.
  • the most potent peptide was the peptide palmitoyl-SEQ ID NO: 31 -NH 2, the TRPM8 receptor blocked by 62%.
  • CHO-TRPA1 Chinese hamster ovary cell line CHO, which stably expresses the mouse TRPA1 receptor (CHO-TRPA1), was monitored by monitoring Ca 2+ signals induced by cinnamaldehyde using a fluorescence plate reader.
  • CHO-TRPA1 cells were cultured in modified Dulbecco Eagle medium (DMEM), supplemented with 10% (v / v) FCS, 100 ⁇ g mL streptomycin and 100 U / mL penicillin. The cells were grown in an incubator with a humid atmosphere at 37 ° C and 5% C0 2 . The cells were dispersed by enzymatic methods and seeded in 96-well plates.
  • DMEM modified Dulbecco Eagle medium
  • Activation of TRPA1 was performed with a pulse of 200 ⁇ cinnamaldehyde at 25 ° C with a microinjector for 10 s.
  • the calcium-sensitive probe Fluo-4 was excited at 500 nm and the emitted fluorescence was filtered with a 535 nm filter.
  • the ionic channel activity was calculated as the difference in fluorescence signal between the baseline (before the addition of the cinnamaldehyde) and the fluorescent signal after the agonist was added.
  • the measurements were normalized with respect to receptor activity in the absence of peptides (vehicle, 0.1% DMSO).
  • the inhibitory activity of the peptides of the invention was evaluated in the CHO-TRPA1 cells by electrophysiology, following the method described in Example 24 and using 200 ⁇ cinnamaldehyde pulses at 25 ° C instead of capsaicin to activate the TRPA1 receptor .
  • Measurements of channel activity were normalized with respect to receptor activity in the absence of peptides (vehicle, 0.1% DMSO).
  • Table 7 details the TRPA1 activity values for those peptides that showed TRPA1 activity inhibition values greater than 15%.
  • the most potent peptide was the Palmitoil-SEQ ID NO: 33-NH 2 peptide, which blocked the TRPA1 receptor by 47%.
  • TRPV1 Activation of TRPV1 in peptidergic sensory neurons leads to the entry of Ca 2+ that activates intracellular signaling cascades and, concomitantly, leads to the release of pro-inflammatory peptides such as substance P and the peptide related to the gene of ocalcitonin ( ⁇ -CGRP).
  • pro-inflammatory peptides such as substance P and the peptide related to the gene of ocalcitonin ( ⁇ -CGRP).
  • ⁇ -CGRP ocalcitonin
  • DRG dorsal root ganglion neurons
  • the cells were resuspended in DMEM supplemented with 10% FBS, 1% penicillin / streptomycin, 1% L-glutamine, 100 ng / mL NGF and 10 ⁇ cytosine arabinoside , and seeded in crystals coated with laminin and polylysine.
  • the cells were grown in an incubator at 37 ° C in a humid atmosphere with 5% C0 2 . All experiments were performed between the third and fourth day of cultivation.
  • Palmitoyl-SEQ ID NO: 16-NH 2 peptide inhibited the release of capsaicin-mediated a-CGRP by 59%.
  • Palmitoil-SEQ ID NO: 16-NH 2 peptide shows inhibitory activity of TRPV1 function in vivo.
  • its effect on electrical discharges caused by harmful stimulation of sensory receptors present in polymodal terminations of nociceptor nerve fibers mediating painful signals in the knee joint was evaluated.
  • the nerve fibers that innervate the knee joint were identified by locating their recipient field, which was determined by the discharge of action potentials from the knee tissue and adjacent tissues in response to the pressure produced with a glass tip [ Gomis A et al. cited ad supra].
  • the mechanical stimuli consisted of rotations of the knee joint inward and outward in the ranges of harmful and normal movement with a duration of 10 s.
  • the experiments shown include complete records in 20 filaments containing between two and five identifiable units.
  • Palmitoil-SEQ ID NO: 16-NH 2 Intra-arterial injection of Palmitoil-SEQ ID NO: 16-NH 2 , followed by washing with saline solution, gradually reduced (average time reduction of about 30 min) the impulse caused by subsequent administrations of capsaicin.
  • Vehicle administration did not affect nerve activity caused by capsaicin or mechanical stimuli.
  • Palmitoyl-peptide SEQ ID NO: 31 showed inhibitory activity -NH 2 function of TRPM8 in vivo. To this end, its effect on electrical discharges caused by harmful stimulation of sensory receptors was evaluated. present in polymodal endings of nociceptor nerve fibers mediating painful signals in the knee joint.
  • a group of 6 adult male rats of the Wistar variety (250-350 g) were anesthetized and subsequently a catheter was inserted into the right saphenous artery for local intraarterial administration of substances in the knee joint.
  • the proximal end of the saphenous nerve was dissected to obtain fine filaments.
  • the nerve fibers that innervate the knee joint were identified by the location of its receptor field, which was determined by the discharge of action potentials of the knee tissue and adjacent tissues in response to the pressure produced with a glass tip.
  • the mechanical stimuli consisted of rotations of the knee joint inward and outward in the ranges of harmful and normal movement with a duration of 10 s [Gomis A. et al. (2007) Pain 130 (1-2): 126-136].
  • the experiments shown include complete records in 20 filaments containing between two and five identifiable units.
  • Palmitoyl-peptide SEQ ID NO: 31 exhibits -NH 2 activity in vivo by modulating the activity of TRPM8 receptors.
  • FIBER ACTIVITY PEPTIDE %
  • EXAMPLE 30 In vivo nerve activity inhibition induced by cinnamaldehyde.
  • Palmitoil-SEQ ID NO: 33-NH 2 peptide showed inhibitory activity of TRPA1 function in vivo. To this end, its effect on electrical discharges caused by harmful stimulation of sensory receptors present in polymodal terminations of nociceptor nerve fibers mediating painful signals in the knee joint was evaluated.
  • a group of 4 adult male rats of the Wistar variety (250-350 g) were anesthetized and subsequently a catheter was inserted into the right saphenous artery for local intraarterial administration of substances in the knee joint.
  • the proximal end of the saphenous nerve was dissected to obtain fine filaments.
  • the nerve fibers that innervate the knee joint were identified by the location of its receptor field, which was determined by the discharge of action potentials of the knee tissue and adjacent tissues in response to the pressure produced with a glass tip.
  • the mechanical stimuli consisted of rotations of the knee joint inward and outward in the ranges of harmful and normal movement with a duration of 10 s [Gomis A. et al. (2007) Pain 130 (1-2): 126-136].
  • the experiments shown include complete records in 20 filaments containing between two and five identifiable units.
  • Palmitoil-SEQ ID NO: 33-NH 2 The intra-arterial injection of Palmitoil-SEQ ID NO: 33-NH 2 , followed by washing with saline solution, gradually reduced (average time reduction of about 20 min) the impulse caused by subsequent administrations of cinnamaldehyde. Vehicle administration (DMSO) did not affect nerve activity caused by cinnamaldehyde or mechanical stimuli. Overall, these results imply that the Palmitoil-SEQ ID NO: 33-NH 2 peptide exhibits anti-nociceptive activity in vivo by modulating the activity of the TRPA1 receptors.
  • FIBER ACTIVITY PEPTIDE (%)
  • Palmitoil-SEQ ID NO: 16-NH 2 compound was explored by evaluating the effect of thermal hyperalgesia and mechanical allodynia produced by plantar administration of CFA.
  • An emulsion of CFA oil / saline solution 1: 1, 0.5 mg / ml
  • Palmitoil-SEQ ID NO: 16-NH 2 5 mg / kg or vehicle (DMSO) was administered intraperitoneally 24 h after CFA injection.
  • Thermal hyperalgesia was monitored 24 hours after CFA injection and up to 6 hours after administering treatments with a dynamic plantar stesiometer from Ugo Basile as described in the literature [Garc ⁇ a-Mart ⁇ nez C. et al. (2006) J. Pain 7 (10): 735-746].
  • the rats were accustomed to an apparatus consisting of individual Perspex boxes on an elevated glass table.
  • a mobile radiant heat source was placed under the table and focused on a rear leg.
  • the leg withdrawal latencies were defined as the time it takes for the rat to remove its hind leg from the heat source.
  • a 25-second cut-off point was set to avoid tissue damage.
  • Mechanical allodynia was followed up to 48 h after administration of treatments (Palmitoil-SEQ ID NO: 16-NH 2 at 5 mg / kg or vehicle) using Von Frey filaments with the "up and down" method [ Garc ⁇ a-Mart ⁇ nez C. et al. (2006) J. Pain 7 (10): 735-746].
  • the rats were placed on a raised wire mesh grid (6 x 6 mm 2 openings) under plastic chambers.
  • filaments with different forces in grams were applied 10 times to the hind leg in an ascending order of strength.
  • the frequency of withdrawal responses was monitored and represented as the percentage of response.
  • the filament was applied for 1 to 2 seconds, with an interval between stimuli of 5 to 10 seconds.
  • Data were also calculated as the area under the curve (AUC), and unilateral ANOVA was used followed by Dunnett's post hoc test as a statistical analysis. Statistical significance was set at p ⁇ 0.05.
  • the Graphpad Prism 5.0 software package was used for statistical analysis.
  • Palmitoil-SEQ ID NO: 16-NH 2 compound was further explored by evaluating the effect on thermal hyperalgesia and chronic pruritus caused by long-term bile duct ligation (BDL).
  • Palmitoil-SEQ ID NO: 16-NH 2 was administered at a dose of 5 mg / kg or vehicle (DMSO) intraperitoneally and activity was monitored up to 72 h after injection.
  • the Hargreaves plantar test was used with conventional equipment (Ugo Basile, Italy) that automatically measured the latency response of the leg withdrawal to a radiant thermal stimulus. To avoid tissue injury in animals that do not respond, stimulation is terminated automatically after 32 s. The latency of the withdrawal of the leg was determined before and after drug or vehicle treatments in rats subjected to BDL and control with simulated operation.
  • the rats were acclimatized for 30 min in a measuring cage, followed by video recording of the scratching behavior for 30 min or 1 h.
  • Spontaneous scratching was quantified by counting the number of scratches in any region of the body performed by the front and rear legs. The data are presented in Figure 3 as mean ⁇ sem with a minimum of six animals per group.
  • Palmitoil-SEQ ID NO: 31 -NH 2 evaluating the effect of cold hyperalgesia caused by plantar administration of CFA.
  • Wistar rats 200-300 g were used for the study.
  • An emulsion of CFA oil / saline solution 1: 1, 0.5 mg / ml was injected into the plantar surface (50 ⁇ ) [Garc ⁇ a-Mart ⁇ nez C. et al. (2006) J. Pain 7 (10): 735-746].
  • Palmitoil-SEQ ID NO: 31-NH 2 (5 mg / kg) or vehicle (DMSO) was administered intraperitoneally 24 hours after CFA injection.
  • Cold hyperalgesia was monitored 24 hours after CFA injection and up to 6 hours after administering treatments by monitoring the behavior of animals after the application of acetone in the homolateral leg [Knowlton WM et al.
  • the evaporative cooling test was performed as follows: the rats were acclimatized for 15 min in an elevated four-compartment chamber with a mesh floor. A syringe was filled with a piece of rubber tube attached to the walls with acetone and the plunger was squeezed so that It will form a small drop of acetone on the top of the tube. The syringe was raised to the rear leg of the rat from below, placing the drop of acetone on the leg. Four rats were tested at the same time with an inter-stimulation period of 4 min per rat, alternating the legs between the stimulations. The responses for subsequent quantification by a blind observer to the experimental conditions were videotaped.
  • Behaviors were scored according to the magnitude of the response along the following scale: 0-no response, 1-brief elevation, sniffing, slap or startle; 2-jump, leg shake; 3-multiple lifts, leg licking; 4-jump, shake, lick or long leg lift; 5-leg protection.
  • the scale was designed so that extreme values (0 and 5) were only produced a few times. Data are represented as the mean ⁇ standard error with a minimum of six animals per group. Statistical significance was evaluated using the Student t test or paired data or independent data and was set at p ⁇ 0.05 using the Graphpad Prism 5.0 software package.
  • Palmitoil-SEQ ID NO: 33-NH 2 compound was explored by evaluating the effect on mechanical allodynia produced by plantar administration of CFA.
  • Wistar rats 200-300 g were used for the study.
  • An emulsion of CFA oil / saline solution 1: 1, 0.5 mg / ml
  • Palmitoil-SEQ ID NO: 33-NH 2 5 mg / kg or vehicle (DMSO) intraperitoneally 24 hours after CFA injection.
  • Mechanical allodynia was followed up to 48 hours after administering the treatments using Von Frey filaments with the "up and down" method.
  • the rats were placed on a raised wire mesh grid (6 x 6 mm 2 openings) under plastic chambers. To quantify the mechanical sensitivity of the legs, filaments with different forces (in grams) were applied 10 times to the hind leg in an ascending order of strength.
  • the frequency of withdrawal responses was monitored and represented as the percentage of response.
  • the filament was applied for 1 to 2 seconds, with an interval between stimuli of 5 to 10 seconds [Garc ⁇ a-Mart ⁇ nez C. et al. (2006) J. Pain 7 (10): 735-746].
  • Data from the area under the curve (AUC) were calculated, and unilateral ANOVA was used followed by Dunnett's post hoc test as a statistical analysis. Statistical significance was set at p ⁇ 0.05.
  • the Graphpad Prism 5.0 software package was used for statistical analysis.

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Abstract

L'invention concerne des peptides qui ont la capacité de moduler l'activité de récepteurs TRP et leur utilisation pour le traitement et/ou la prévention de la douleur, l'inflammation, le prurit, des maladies et/ou troubles des voies respiratoires et/ou des maladies et/ou troubles associés à des déséquilibres en calcium.
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WO2013080830A1 (fr) * 2011-11-28 2013-06-06 花王株式会社 Agent de refroidissement et activateur de trpm8
US8722669B2 (en) 2009-12-08 2014-05-13 Case Western Reserve University Compounds and methods of treating ocular disorders
ES2532749R1 (es) * 2013-09-30 2015-05-06 Universidad Miguel Hernández De Elche Péptidos bloqueantes de termorreceptores y sus usos
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
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US10159268B2 (en) 2013-02-08 2018-12-25 General Mills, Inc. Reduced sodium food products
US10172797B2 (en) 2013-12-17 2019-01-08 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
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CN109364050A (zh) * 2018-10-19 2019-02-22 大连医科大学 艾地苯醌在制备治疗肺动脉高压药物中的应用
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