CN117624301A - Synthetic peptide for inhibiting generation of staphylococcus aureus toxin with low toxicity in vivo and application thereof - Google Patents
Synthetic peptide for inhibiting generation of staphylococcus aureus toxin with low toxicity in vivo and application thereof Download PDFInfo
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- CN117624301A CN117624301A CN202210982362.XA CN202210982362A CN117624301A CN 117624301 A CN117624301 A CN 117624301A CN 202210982362 A CN202210982362 A CN 202210982362A CN 117624301 A CN117624301 A CN 117624301A
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- 241000191967 Staphylococcus aureus Species 0.000 title claims abstract description 37
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- 231100000765 toxin Toxicity 0.000 title claims abstract description 18
- 238000001727 in vivo Methods 0.000 title claims abstract description 12
- 231100000053 low toxicity Toxicity 0.000 title claims abstract description 10
- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 8
- 238000004519 manufacturing process Methods 0.000 claims abstract description 13
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- 239000003814 drug Substances 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims description 14
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/10—Peptides having 12 to 20 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/64—Cyclic peptides containing only normal peptide links
Abstract
The invention provides a synthetic peptide for inhibiting the generation of staphylococcus aureus toxin with low toxicity in vivo and application thereof. The structure of the synthetic peptide is as follows: CH (CH) 3 (CH 2 ) 10 CO‑G‑(CQHwWHWYC)‑DDD‑NH 2 . The synthetic peptide specifically binds to the RNAIII activator protein secreted by the staphylococcus aureus and inhibits toxin production of the staphylococcus aureus, and has no obvious toxicity after intravenous administration of the synthetic peptide through mice. The invention also relates to application of the synthetic peptide in preparing medicaments for resisting staphylococcus aureus infection.
Description
Technical Field
The invention relates to a synthetic peptide for inhibiting the generation of staphylococcus aureus toxin with low toxicity in vivo and application thereof.
Background
Staphylococcus aureus (golden grape bacteria) is a common gram-positive pathogen and one of the main microorganisms for causing fatal diseases such as burn injury, war injury infection, pneumonia, endocarditis, septicemia, toxic shock and the like. The number of people infected with staphylococcus aureus in hospitals exceeds millions each year, and the clinical treatment of staphylococcus aureus mostly adopts a method of combining antibiotics, but the effect is not ideal. Because staphylococcus aureus is extremely easy to generate drug resistance and has no good solution, a plurality of antibiotics commonly used are ineffective, and the control of staphylococcus aureus infection is one of the problems to be solved in clinical medicine.
The main pathogenic substances of the staphylococcus aureus are toxins, including hemolytic toxins, leukocidal agents, enterotoxins and the like. Recent studies have shown that the synthesis of these virulence factors by Staphylococcus aureus is controlled by a regulatable RNA molecule, RNAIII, which activates gene transcription of the virulence factors and regulates translation of the virulence factors. RNAIII levels are low in the early log phase of bacterial growth, but increased 40-fold to the late log phase, and RNAIII levels are regulated by proteins secreted by the Staphylococcus aureus itself, namely RANIII activator protein (RNA III activating protein, RAP), so RAP is also known as a Staphylococcus aureus virulence stimulator. The staphylococcus aureus continuously secretes the RAP, and only after the RAP reaches a certain concentration, the staphylococcus aureus has the effect of activating the production of virulence factors. The staphylococcus aureus without RAP production is not pathogenic itself. The results of the research published in the journal of Science by Balaban et al, 1998, show that animals immunized with RAP prepared from them can be effectively protected from infection by Staphylococcus aureus by antibodies (Balaban N, et al Autoincer of virulence as a target for vaccine and therapy against Staphylococcus auto. Science,1998,280 (17): 438-440).
The inventor prepares the sequence general formula as follows: CH (CH) 3 (CH 2 ) Chemical synthesis of modified peptide MRG of m-X-G- (CQHwWWYC) - (R) n-Y. MRG is extremely soluble in water and has good anti-Staphylococcus aureus activity. MRG has obtained US patent (US 10905735B 2) and chinese invention patent (zl201780021188. X). As a result of intensive studies, it was found that intravenous administration of greater than 15mg/kg body weight resulted in significant convulsions and even death, and intravenous administration of greater than 75mg/kg body weight was stillPulse administration causes complete death of mice, and has obvious influence on the drug-forming property. Thus, there remains a need for synthetic peptides that inhibit the production of staphylococcus aureus toxin with low toxicity in vivo.
Disclosure of Invention
In view of the drawbacks of the prior art, a main object of the present invention is to improve the in vivo toxicity and maintain the biological activity of the modified peptides of the prior art.
Thus, the present invention provides a novel synthetic peptide MUS-1 based on MRG sequence modification. The results show that the modified chemically synthesized peptide MUS-1 is not only extremely soluble in water compared with MRG, but also has good anti-staphylococcus aureus activity, and the intravenous administration (100 mg/kg body weight) in the tail of the mice has no obvious toxicity.
The chemically synthesized peptide MUS-1 is modified based on MRG sequence, so that the action mechanism is consistent with MRG, namely, the chemically synthesized peptide MUS-1 specifically binds with the autocrine RNAIII activator protein of staphylococcus aureus and inhibits the toxin production of the staphylococcus aureus, and no obvious toxicity is seen after the in vivo administration of the chemically synthesized peptide MUS-1 in mice.
The chemically synthesized peptide MUS-1 is completely new from a source or structurally, and is not reported in any literature.
It is therefore an object of the present invention to provide a synthetic peptide which inhibits the production of a staphylococcus aureus toxin with low toxicity in vivo, which is chemically synthesized. The synthetic peptide can specifically inhibit the production of the staphylococcus aureus toxin.
The invention provides a chemical synthesis in vivo low toxicity synthetic peptide for inhibiting the generation of staphylococcus aureus toxin, which is a small molecule polypeptide analogue and has the following structural formula:
CH 3 (CH 2 ) 10 CO-G-(CQHwWHWYC)-DDD-NH 2
wherein:
g represents: glycine residues;
(CQHwWWYC): c represents: an L-cysteine residue; q represents: an L-glutamine residue; h represents: an L-histidine residue; w represents: an L-tryptophan residue; w represents: d-tryptophan residues; y represents: l-tyrosine residues;
d represents: an L-aspartic acid residue;
the two cysteine residues represented by C are linked by a disulfide bond.
Preferably, the method comprises the steps of,
g represents: a natural L-glycine residue;
(CQHwWWYC): c represents: a natural L-cysteine residue; q represents: natural L-glutamine residues; h represents: an L-histidine residue; w represents: natural L-tryptophan residues; w represents: d-isomer of natural tryptophan; y represents: natural L-type tyrosine residues;
d represents: natural L-aspartic acid residues.
Preferably, the chemically synthesized peptide MUS-1 is capable of specifically binding to Staphylococcus aureus virulence stimulating factor RAP.
Preferably, the chemically synthesized peptide MUS-1 is capable of inhibiting the production of staphylococcus aureus toxins.
Preferably, the chemically synthesized peptide MUS-1 is obtained by chemical synthesis.
Preferably, the chemically synthesized peptide MUS-1 has low toxicity in vivo.
CH 3 (CH 2 ) 10 CO-is dodecanoyl.
Another object of the present invention is to provide the use of the above synthetic peptide inhibiting the production of staphylococcus aureus toxin with low toxicity in vivo for preparing a medicament against staphylococcus aureus infection.
Furthermore, the present invention provides a method of treating a disease associated with a staphylococcus aureus infection, the method comprising administering to a patient a therapeutically effective amount of the above-described chemically synthesized peptide MUS-1.
Preferably, the disease includes burn and war wound infection, pneumonia, endocarditis, septicemia and toxic shock caused by staphylococcus aureus infection.
In addition, the invention provides a pharmaceutical composition which comprises the chemical synthetic peptide MUS-1 and pharmaceutically acceptable auxiliary materials.
The reason for the drug resistance of traditional antibiotic treatment is mainly that bacteria produce induced enzymes which decompose the effective groups in antibiotics under the pressure of survival after the administration. The invention utilizes the polypeptide compound which specifically inhibits the RAP activity to establish a scheme for treating the staphylococcus aureus infection, and finds a new way for treating the common, multiple and fatal diseases which always plague clinical drug-resistant staphylococcus aureus infection.
The invention has important significance for developing novel micromolecular polypeptide medicines for resisting staphylococcus aureus infection, and has wide application value and broad market prospect.
In this application, "synthetic peptide", "chemically synthesized peptide", "cyclic heptapeptide modified compound MUS-1", "MUS-1" have the same meaning.
Drawings
FIG. 1 is a scheme showing the synthetic procedure for the synthetic peptide MUS-1 of the present invention.
FIG. 2 is an HPLC analysis chart of the synthetic peptide MUS-1 of the present invention.
FIG. 3 is a MS analysis chart of the synthetic peptide MUS-1 of the present invention.
Detailed Description
The present invention will be described in further detail with reference to examples.
MUS-1:CH 3 (CH 2 ) 10 CO-G-(CQHwWHWYC)-DDD-NH 2
The molecular formula: c (C) 91 H 112 N 22 O 22 S 2
Molecular weight: 1930.13
Example 1: preparation of cyclic heptapeptide modified compound MUS-1
1. Synthetic peptide sequence: CH (CH) 3 (CH 2 ) 10 CO-G-(CQHwWHWYC)-DDD-NH 2 (molecular weight: 1930.13)
2. Synthetic procedure (see FIG. 1, synthetic procedure roadmap for synthetic peptide MUS-1 of the invention):
step one: 5mmol MUS-1 is synthesized, the substitution degree of Rink Amide-AM Resin is selected to be 0.45mmol/g, the amount of Resin is weighed according to a formula=the synthetic molar amount/substitution degree of Resin, namely 11.11g of Resin Rink Amide-AM Resin (5 mmol/0.45 mmol/g) is needed to be weighed, the weighed Resin is put into a reaction column and swelled for about 30min by N, N-Dimethylformamide (DMF), and the swelled liquid is taken out and then washed 3 times by using DMF as a washing solution.
Step two: the deprotecting reagent (V) Piperidine compounds :V DMF =1:4) is added into the resin swelled in the step one to react with nitrogen, the reaction is carried out for 5min and 15min respectively, and indene detection reagent is adopted after deprotection and washing: (a) 5% ninhydrin in absolute ethanol (w/v); (b) phenol: absolute ethanol solution (4:1, w/v); (c) pyridine. Two drops of each detection reagent are dripped, the color is observed by heating for 3-5min at 105 ℃, if the color is blue, the protection liquid can be pumped out, and if the color is not developed, the deprotection is not thorough, and the reason is immediately ascertained and removed again. After deprotection, fmoc-Asp (OtBu) -OH and a condensation reagent 1-hydroxybenzotriazole (HOBt) and N, N' -Diisopropylcarbodiimide (DIC) are added after DMF is washed for six times for coupling reaction (the coupling sequence is from C end to N end according to peptide sequence, fmoc-protected amino acids are coupled one by one) for 2-3h. After the reaction is finished, detecting whether the reaction is complete by using an ninhydrin color reaction experiment, namely, dripping a small amount of resin into a detection tube, heating each solution of the three detection solutions at 105 ℃ for 3-5min to observe the color of the solution, and if the reaction is complete through colorless indication, otherwise, indicating that the reaction is incomplete, and adding materials or repeating until the reaction is complete. And (3) coupling the amino acids in the peptide sequence in sequence by analogy according to the method to obtain the amino acid sequence:
Gly-Cys(Trt)-Gln(Trt)-His(Trt)-D-Trp(Boc)-Trp(Boc)-His(Trt)-Trp(Boc)-Tyr(tBu)-Cys(Trt)-Asp(OtBu)-Asp(OtBu)-Asp(OtBu)-Rink Amide-AM Resin
step three: in the second step, the peptide is coupled to Gly, and the last amino acid, namely dodecanoic acid (lauric acid) is coupled under the condition of removing protecting groups, and the adopted condensation reagent is 1-Hydroxybenzotriazole (HOBT), benzotriazole-N, N, N ', N' -tetramethylurea Hexafluorophosphate (HBTU) and N, N-Diisopropylethylamine (DIPEA), and the reaction time is about 1h. Detecting whether the reaction is complete by adopting an ninhydrin color development method, washing the resin for 3-4 times by using DMF after the reaction is complete, shrinking the resin by using methanol (MeOH) for three times, wherein the shrinking time of each time is 10min, and then vacuum drying the resin until the resin is in a quicksand shape to obtain the linear peptide resin of the target peptide:
CH 3 (CH 2 ) 10 CO-Gly-Cys(Trt)-Gln(Trt)-His(Trt)-D-Trp(Boc)-Trp(Boc)-His(Trt)-Trp(Boc)-Tyr(tBu)-Cys(Trt)-Asp(OtBu)-Asp(OtBu)-Asp(OtBu)-Rink Amide-AM Resin
step four: and (3) taking out the sandy peptide resin obtained in the step (III), weighing 25.1g, firstly preparing 200mL of conventional cracking reagent according to the ratio of TFA to phenylthioether to EDT to anisole=90:5:3:2, shaking uniformly, adding 8-10mL of the cracking reagent into each 1g of peptide resin for cracking, and reacting for about 2-3 hours. After the reaction, filtering the resin to obtain about 200mL of filtrate (with partial loss in filtration), slowly adding the filtrate into anhydrous diethyl ether according to a sedimentation ratio of 1:8 (filtrate: methyl tertiary butyl ether), standing for 30min, and obtaining linear crude peptide through centrifugation, washing and drying after full sedimentation:
CH 3 (CH 2 ) 10 CO-Gly-Cys-Gln-His-D-Trp-Trp-His-Trp-Tyr-Cys-Asp-Asp-Asp-NH 2 after drying, 8.71g of crude peptide was obtained.
Step five: grinding the dried linear crude peptide obtained in the step four to powder, dissolving the powder by pure water, and obtaining the total 2500mL of linear crude peptide solution with the concentration of 1mmol/500mL, and taking out a small sample for HPLC analysis to locate the peak time.
Step six: an ethanol solution of iodine (5 g of iodine is taken and put into 1L of water for dissolution) is added dropwise into the linear crude peptide solution in the fifth step until the solution becomes pale yellow, and the solution is put into a water bath with the temperature of 50 ℃ and stirred for 1h. The solution is regulated to be clear by Vc (10 g of Vc is taken and put into 1L of water for dissolution) aqueous solution, and crude peptide product solution is obtained, namely:
CH 3 (CH 2 ) 10 CO-Gly-Cyclo(Cys-Gln-His-D-Trp-Trp-His-Trp-Tyr-Cys)-Asp-As p-Asp-NH 2
step seven: subjecting the crude peptide of interest after the cyclization in the step six to HPLC analysis to C 18 Separating and purifying by reversed phase high performance liquid chromatography column, and lyophilizing by rotary evaporation to obtain the final product of target peptide. The method mainly comprises the following steps:
the cyclized crude peptide solution was filtered through a 0.45 μm filter membrane, and the filtrate was adjusted to pH4-5 and purified by HPLC.
The HPLC analytical instrument was: DIONEX U3000, analytical column: c (C) 18 、5μm、4.6X1250 mm, analysis conditions: mobile phase: phase A: 1% TFA, phase B: acetonitrile; innovative 5cm preparative HPLC, filler C, was used for purification 18 、10μm、/>150×250mm。
The crude solution after filtration was purified using 5cm prep HPLC with mobile phase: phase A: TFA (1 mL TFA in 1000mL water), phase B: 100% acetonitrile; detection wavelength: λ=230 nm; column temperature: room temperature; collecting a sample by using a clean triangular flask, collecting a purified solution with the purity of more than 98% and less than 1% as a qualified product, repeating the steps above for unqualified samples, completely treating the solution, merging the qualified purified solution, and concentrating by vacuum rotary evaporation.
Step eight: and (3) freeze-drying the concentrated solution packaged in the previous step to obtain white powder, thus obtaining the finished product.
Pre-freezing: firstly, pre-freezing the concentrated sample solution, namely, placing the sample on a partition board in a freeze-drying box for pre-freezing, and keeping the temperature of the product below-40 ℃ for about 120min.
Sublimation drying: the electrical heating was set to 0℃for a bias time of 1min and maintained for about 40min. The electrical heating was set at 10℃with a deviation time of 500min. The electrical heating was set at 35℃and the deflection time was 420min.
Desorption: the temperature was raised to about 33℃and maintained for about 240 minutes.
Step nine: purity identification and structure determination of chemically synthesized MUS-1.
HPLC analysis is carried out on the synthesized and prepared cyclic heptapeptide modified compound MUS-1, and the purity is more than 98 percent (see figure 2, which is an HPLC analysis chart of the synthesized peptide MUS-1); MUS-1 theoretical molecular weight 1930.13, mass Spectrometry molecular weight 1930.1 ([ M+2H)] 2+ 966.0,[M+H] + 1931.1. FIG. 3 is an MS analysis map of synthetic peptide MUS-1).
TABLE 1 HPLC analysis data for synthetic peptide MUS-1
Example 2: inhibition of the production of Staphylococcus aureus in vitro by the Cycloheptapeptide modified Compounds MUS-1 and MRG
1. Experimental reagent, consumable and instrument
Cycloheptapeptide modified compound MRG (CH) 3 (CH 2 ) 10 CO-G-(CQHwWHWYC)-RRR-NH 2 ) And a cyclic heptapeptide modified compound MUS-1 (CH) 3 (CH 2 ) 10 CO-G-(CQHwWHWYC)-DDD-NH 2 ) Is synthesized by Tianji biological pharmaceutical Co., ltd, and has purity of more than 98%. Golden strain 04018: provided by Beijing basic medical research institute; platelets (fresh blood agar plates) were purchased from beijing australian biotechnology liability company, BHI plate home made; inlet BHI Medium (BactoTM Brain Heart Infusin) was purchased from BD company, USA; DMEM medium was purchased from CIBCO company, usa; imported fetal bovine serum was purchased from PAN bio corporation, usa; 0.22 μmembranes were purchased from PALL, U.S.A.; MDBK cells were supplied by the basic medical institute of beijing; desk-top centrifuge: EPPDORF, germany; enzyme-linked instrument: from MICROPLATE corporation of the united states; cell culture flasks were purchased from CORNING corporation, usa.
2. Experimental method
Reference (Yang G, et al A novel peptide screened by phage display can mimic TRAP antigen epitope against Staphylococcus aureus Infection J biol. Chem.2005, 280:27431-27435) to methods for determining the level of inhibition of production of gold toxins is described in detail as follows:
(1) Taking a staphylococcus aureus strain 04018 frozen in a refrigerator at the temperature of-70 ℃, and streaking into a blood plate or a BHI plate; after culturing for 16h in a 37 ℃ incubator, monoclonal grows out in the observation plate, and the observation plate is placed in a refrigerator at 4 ℃ for standby;
(2) After 8 hours, randomly picking a monoclonal colony in a flat plate in an ultra-clean bench, and inoculating the monoclonal colony into a 5mL BHI culture medium test tube, and picking 2 tubes in total; shaking table at 37 deg.c and 200rpm, collecting bacteria after 16 hr, and mixing the 2 tubes of bacteria liquid;
(3) The chemically synthesized peptide MRG, MUS-1 and positive control (Staphylococcus aureus toxin inhibitor protein TP) are dissolved in physiological saline respectively, diluted to different concentrations and added into bacterial BHI culture medium. The negative control group is a staphylococcus aureus BHI culture medium; a control group of normal cells plus BHI medium was also set.
(4) Incubating chemical synthetic peptides with different concentrations with staphylococcus aureus 04018, culturing for 6 hours, collecting bacteria, respectively taking 700 mu L of bacterial suspension according to the number, adding into an EP tube, centrifuging at 8000rpm for 5min, taking supernatant, boiling at 100 ℃ for 7min, and centrifuging at 14000rpm for 10min; 10. Mu.L of supernatant was added to the solution and inoculated 1X 10 in advance 5 96-well cell culture plates of/mL MDBK cells; after further culturing for 18-20 hours, 5. Mu.L/well of MTT solution (5 mg/mL) was added, and after 3 hours, 100. Mu.L/Kong Zhongzhi of 10% SDS+0.01M HCl solution was added. After incubation at 37℃for 20h, detection and reading were performed at 595nm by ELISA.
3. Experimental results and conclusions
Experimental results show that the cyclic heptapeptide modified compound MUS-1 can be well dissolved in physiological saline; the chemical synthetic peptide can well inhibit the generation of staphylococcus aureus, has obvious protection effect on the proliferation inhibition of MDBK cells caused by the staphylococcus aureus, and has a certain dose-effect relationship. In vitro inhibition of the gold staphylotoxin activity by MUS-1 was comparable to MRG (Table 2).
TABLE 2 inhibition of Staphylococcus aureus toxin production in vitro by MUS-1 and MRG
Example 3: observation of survival number of mouse tail vein administered with cyclic heptapeptide modified compound MUS-1 and MRG
1. Experimental reagent, consumable and instrument
Cycloheptapeptide modified compound MRG (CH) 3 (CH 2 ) 10 CO-G-(CQHwWHWYC)-RRR-NH 2 ) And a cyclic heptapeptide modified compound MUS-1 (CH) 3 (CH 2 ) 10 CO-G-(CQHwWHWYC)-DDD-NH 2 ) Are all chemically synthesized by Tianji biopharmaceutical Co-Ltd, tianma medicine group in Suzhou, and have the purity of more than 95 percent. MRG and MUS-1 were dissolved in physiological saline and diluted to different concentrations. BALB/c mice35 females, 8 weeks) were purchased from velocin.
2. Experimental method
The mice were injected with MRG and MUS-1 at different concentrations in their tail veins, and the activity status of the mice after drug injection was observed and the survival of the mice was recorded within one week.
3. Experimental results
Experimental results show that the cyclic heptapeptide modified compound MUS-1 has good activity state of mice when the intravenous injection dose reaches 100mg/kg body weight, no obvious bad state, and survives for one week and grows normally. Intravenous injection of MRG at a dose greater than 15mg/kg body weight in the tail of mice resulted in significant twitching, restricted movement, shortness of breath, and intravenous administration of greater than 75mg/kg body weight resulted in total death of the mice (Table 3).
TABLE 3 observation of survival of MUS-1 and MRG mice administered by tail vein
Based on the above description of the invention, one skilled in the art could fully apply the invention, and all such modifications as are intended to be included within the scope of the present invention.
Claims (10)
1. A peptide has the structural formula:
CH 3 (CH 2 ) 10 CO-G-(CQHwWHWYC)-DDD-NH 2
wherein:
g represents: glycine residues;
(CQHwWWYC): c represents: an L-cysteine residue; q represents: an L-glutamine residue; h represents: an L-histidine residue; w represents: an L-tryptophan residue; w represents: d-tryptophan residues; y represents: l-tyrosine residues;
d represents: an L-aspartic acid residue;
the two cysteine residues represented by C are linked by a disulfide bond.
2. The peptide according to claim 1, wherein,
g represents: a natural L-glycine residue;
(CQHwWWYC): c represents: a natural L-cysteine residue; q represents: natural L-glutamine residues; h represents: an L-histidine residue; w represents: natural L-tryptophan residues; w represents: d-isomer of natural tryptophan; y represents: natural L-type tyrosine residues;
d represents: natural L-aspartic acid residues.
3. The peptide of claim 1, wherein the peptide is capable of specifically binding to staphylococcus aureus virulence stimulus factor RAP.
4. The peptide of claim 1, wherein the peptide is capable of inhibiting staphylococcus aureus toxin production.
5. The peptide according to claim 1, wherein the peptide is obtained by chemical synthesis.
6. The peptide of claim 1, wherein the peptide is of low toxicity in vivo.
7. Use of the peptide of claim 1 for the preparation of a medicament against a staphylococcus aureus infection.
8. A method of treating a disease associated with a staphylococcus aureus infection, the method comprising administering to a patient a therapeutically effective amount of the peptide of claim 1.
9. The method of claim 8, wherein the disease comprises burns and war wound infection caused by staphylococcus aureus infection, pneumonia, endocarditis, septicemia, toxic shock.
10. A pharmaceutical composition comprising the peptide of claim 1, and a pharmaceutically acceptable adjuvant.
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