NL2025303B9 - Coronavirus targeting drugs - Google Patents

Abstract

The invention relates to compounds and to their medical use. Exemplary medical uses are the prevention and treatment of coronaVirus infections, such as SARS-CoV—Z infection. The compounds comprise at least two peptides that are physically linked through a linker, wherein each peptide comprises an amino acid sequence TFLDKFNHEAEDLFYQ or a variant thereof.

Description

P126846NL00 Title: CORONAVIRUS TARGETING DRUGS The invention relates to compounds and to their medical use.

Exemplary medical uses are the prevention and treatment of coronavirus infections, such as SARS-CoV-2 infection. The compounds comprise at least two peptides that are physically linked through a linker, wherein each peptide comprises an amino acid sequence TFLDKFNHEAEDLFYQ or a variant thereof.

In one aspect the invention relates to the use of compounds according to the invention in medical applications, particularly such as the treatment of coronavirus infections, by affecting the binding of the viral spike protein to a virus receptor of potential host cells.

Coronaviruses are known to cause diseases in mammals and birds, in particular infections to the respiratory tract. Whereas some coronaviruses, in particular human coronaviruses (HCoV), are typically responsible for common colds, other coronaviruses, such as Middle East respiratory syndrome-related coronaviruses (MERS) and severe acute respiratory syndrome-related (SARS) coronaviruses can be lethal.

A new coronavirus, which emerged in Wuhan, has resulted in a pandemic in early 2020. This severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2), and the disease caused by it (COVID-19) is primarily lethal to aged patients with pre-existing medical conditions. The development of anti-coronavirus drugs is highly urgent as there is a great demand for such specific drugs, in particular to slow the SARS-CoV-2 pandemic and treat infected patients.

Studies aiming at developing coronavirus vaccines and anti-coronavirus therapies are diverse in the sense that varying viral targets or different stages of the disease are targeted. One such approach is directed to inhibitors of the so-called spike protein. Various attempts have been made to design spike protein inhibitors as a suitable starting point for further coronavirus disease treatment studies.

For example, Zhang ef al. (2020), bioRxiv (https://www.blorxiv.org/content/10.1101/2020.03.19.999318v1) relates to a chemically synthesized monomeric compound comprising 23-mer peptide fragment of an angiotensin-converting enzyme 2 (ACE2) peptidase domain (PD) al helix composed entirely of proteinogenic amino acids.

It is an objective of the invention to provide compounds that are suitable for use in medical applications, in particular with respect to inhibiting coronavirus infections, such as SARS-CoV-2 infections.

The inventors found that one or more of these objectives can, at least in part, be met by providing the compounds as described herein.

Accordingly, in a first aspect of the invention there is provided a compound, comprising at least two peptides that are physically linked through a linker, wherein each peptide comprises an amino acid sequence TFLDKFNHEAEDLFYQ or a variant thereof.

In a further aspect of the invention, there is provided a pharmaceutical composition comprising a compound as described herein.

In yet a further aspect of the invention, there is provided a compound as described herein for use as a medicament.

In yet a further aspect of the invention, there is provided a compound as described herein, such as the compound as described herein for use as a medicament, for use in the prevention or treatment of an infection caused by coronavirus.

In yet a further aspect of the invention, there is provided a method for inhibiting infection of a cell that is permissive for coronavirus, comprising: - providing the cell with a compound as described herein or a pharmaceutical composition as described herein.

In yet a further aspect of the invention, there is provided a method for treating an infection caused by a virus that can enter a cell via the ACE2 receptor, preferably a coronavirus in an individual, comprising: - administering a compound as described herein or a pharmaceutical composition as described herein to the individual.

In yet a further aspect of the invention, there is provided a method for treating an infection caused by a coronavirus in an individual, comprising: - administering a compound as described herein or a pharmaceutical composition as described herein to the individual.

When referring to a noun (e.g., compound, virus, virion, etc.) in the singular, the plural is meant to be included, or it follows from the context that it should refer to the singular only.

The term “alkyl” as used herein is meant to include optionally substituted straight (or linear) and branched chain alkyl groups that are saturated (i.e., no double or triple bonds present). The alkyl groups may have 1-20 carbon atoms. The alkyl groups may comprise one or more heteroatoms. In particular, the alkyl groups have 1-12 carbon atoms, such as 1-8 carbon atoms. Preferably, the alkyl groups have 1-6 carbon atoms.

The term also encompasses n-alkyl, zs0-alkyl (or i-alkyl), tert-alkyl (¢-alkyl), neo-alkyl, and anteisoalkyl groups. Substituted alkyl groups can be substituted with one or more substituents (e.g., substituents as described herein), such as amino, hydroxyl, cyano, carboxy, nitro, thio, alkoxy and/or halogen groups.

The term “alkenyl” as used herein is meant to include optionally substituted linear and branched chain and (poly)cyclic alkenyl groups having one or more double bonds. The alkenyl groups may have 2-20 atoms. The alkenyl groups may comprise one or more heteroatoms. In particular, the alkenyl groups can have 2-12 carbon atoms, such as 2-8 carbon atoms.

Preferably, the alkenyl groups have 2-6 carbon atoms. (Poly)cyclic alkenyl groups having one or more double bonds can have 3-12 ring members, such as 3, 5, 6, or 7. Preferably, (poly)cyclic alkenyl groups have 5, 6 or 7 ring members. The (poly)cyclic alkenyl groups may comprise one or more heteroatoms, such as oxygen, nitrogen, and/or sulfur. In particular, hetero(poly)cyclic alkenyl groups have 2-20 atoms of which 1-10 are heteroatoms, such as 2-12 atoms of which 1-6 are heteroatoms. Preferably, the hetero(poly)cyclic alkenyl groups have 2-8 atoms of which 1-4 are heteroatoms. Examples of cycloalkenyl groups include polycyclic ring structures as described herein having at least one double bond.

The term “alkynyl” as used herein is meant to include optionally substituted linear and branched alkyl groups having one or more triple bonds. The alkynyl groups may have 2-20 carbon atoms. The alkynyl groups may comprise one or more heteroatoms. In particular, the alkynyl groups can have 2-15 carbon atoms. Preferably, alkynyl groups have 2-10 carbon atoms, such as 2, 3, 4, 5, or 6.

The term “aryl” as used herein is meant to include optionally substituted monocyclic, bicyclic and polycyclic (e.g., having 2, 3 or 4 rings that can be fused) aromatic hydrocarbon groups. The aryl groups may comprise one or more heteroatoms. The aryl groups may have 5-20 carbon atoms. In particular, the aryl groups can have 5-10 carbon atoms. Preferably, the aryl groups have 5 or 6 carbon atoms. The term “aryl” is also meant to include substituted aromatic hydrocarbons, that can be monosubstituted or substituted more than once, such as 2-, 3-, 4-, 5-, or 6- substituted, or di-substituted.

The term “compound”, in particular in the case of the compound according to the invention, is meant to include all possible atropisomers, stereoisomers, diastereomers, optical stereoisomers, tautomers, as well as mixtures thereof, including racemic mixtures. Depending on the desired use of the compound, a pure compound, racemic mixture, or mixture having varying isomer ratios may be selected. The term also includes solvates, such as hydrates, as well as anhydrous and non-solvated forms. Also, the term includes all isotopes of atoms occurring in the intermediate compounds and/or (final) compounds (products). The compound may also exist as a solvate, z.e., a compound in a composition with solvent molecules. In that 5 case, the composition includes solvent in stoichiometric quantities, such as a monosolvate or a disolvate, or can include solvent in random amounts. In case the solvent 1s water, the term “solvate” may be read as “hydrate”.

The term “cycloalkyl” as used herein is meant to include optionally substituted, partly saturated, and completely saturated non-aromatic cyclic hydrocarbons. The cycloalkyl groups can have up to 20 ring-forming atoms. In particular, the cycloalkyl groups may predominantly comprise carbon atoms, and optionally contain one or more heteroatoms, such as oxygen, sulfur, and nitrogen as part of the cycle. The cycloalkyl groups can have 3-12 ring members, such as 3, 4, 5, 6 or 7.

Cycloalkyls include mono- or polycyclic ring structures, such as fused ring systems, bridged ring systems and spiro ring systems. Cycloalkyl groups also include rings that are substituted with linear or branched chain alkyl groups as defined herein. Examples of substituted cycloalkyl groups can be mono-substituted or substituted more than once, such as 2,2-, 2,3-, 2,4-, 2,5- or 2,6-disubstituted cyclohexyl groups or mono-, di- or tri-substituted polycyclic groups, which can be substituted with, for example, amino, hydroxyl, cyano, carboxy, nitro, thio, alkoxy, and/or halogen groups.

The term “haloalkyl” as used herein is meant to include optionally substituted mono-halo alkyl groups and poly-halo alkyl groups wherein all halo atoms can be the same or different, and per-halo alkyl groups, wherein all hydrogen atoms are replaced by halogen atoms. The haloalkyl groups may comprise one or more heteroatoms.

The term “heteroatom” as used herein is meant to refer to an atom other than hydrogen or carbon. In particular, the heteroatom can be an oxygen atom, a sulfur atom, a nitrogen atom, a phosphorus atom, or a boron atom.

Preferably, the heteroatom is a trivalent atom, such as nitrogen atom or boron atom.

More preferably, the heteroatom is nitrogen atom.

The term “heteroalkyl” as used herein is meant to include optionally substituted linear or branched chain alkyl groups consisting of a number of carbon atoms and at least one heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur.

In particular, heteroalkyl groups can have 1-20 carbon atoms and/or 1-10 heteroatoms, such as 1-12 carbon atoms and/or 1-8 heteroatoms.

Preferably, the heteroalkyl groups have 1-8 carbon atoms and/or 1-4 heteroatoms.

The nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quarternized (i.e., four substituents each having a carbon bond to the nitrogen atom, substituted ammonium groups, or salts). The heteroatom may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the moiety to which 1t1s attached, as well as attached to a distal carbon atom, such as the most distal one, in the heteroalkyl group.

The term “heteroaryl” as used herein is meant to include optionally substituted aromatic heterocycles having, for example, ring-forming atoms (particularly mostly carbon atoms) and having at 20 least one heteroatom ring member, such as a sulfur atom, an oxygen atom, or a nitrogen atom.

The term includes monocyclic and polycyclic (e.g. having 2, 3 or 4 fused rings) systems.

The term “heterocycloalkyl” as used herein is meant to include optionally substituted non-aromatic heterocyclic alkyls that can have up to 20 ring-forming atoms.

Exemplary heterocycloalkyl groups are cyclic alkyls, cyclic alkenyls, and cyclic alkynyls having one or more of the ring-forming carbon atoms replaced by a heteroatom, such as oxygen, nitrogen, and/or sulfur atom.

Heterocycloalkyls can be mono or polycyclic (e.g., fused, bridged, or spiro) systems.

Also included by the term are functional groups that have one or more aromatic rings fused (i.e., having a bond in common) to a non-aromatic heterocyclic ring.

The phrase “in need thereof” as used herein is meant to include that a subject has been identified as having a need for the particular method or treatment. The identification of such a need can be by any means of diagnostics. In particular, in any of the methods and treatments described herein, the subject is in need thereof.

The term “individual” as used herein is meant to include the human and animal body, preferably the human body. The term is meant to be interchangeable with “subject” and “patient”. The term “animal” is meant to exclude humans, and to include non-humans, such as vertebrates, e.g., wild, domestic, and farm animals.

The phrase “optionally substituted” as used herein is meant to refer to the optional presence of one or more substituents, such as the substituents as described herein.

The terms “prevention” and “preventing” as used herein are meant to refer to a reduction of the risk of acquiring a particular infection, disease, condition, or disorder.

The term “substituent” as used herein is meant to refer to an organic group, such as a heteroatomic organic group, or a halogen that substitutes at least one atom or one atomic group of another molecule. For example, a hydrogen bond present in a molecule may be replaced by a bond to a non-hydrogen atom which originates from a(n) (indicated) substituent. Exemplary bonds to a non-hydrogen atom include bonds to a halogen atom, a carbon atom or an oxygen atom. These can include groups such as hydroxyl groups, alkoxy groups, aryloxy groups, arylalkoxy groups, oxo(carbonyl) groups, carboxyl groups, such as carboxylic acids, carboxylates, and carboxylate esters, a sulfur atom in groups, such as thiol groups, thioalkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups, a nitrogen atom in groups, such as amines, hydroxylamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines, a carbon atom in groups, such as those described herein such as alkyl groups such as methyl, ethyl, propryl or butyl groups and aryl groups, cycloalkyl groups, alkenyl groups, alkynyl groups, alkoxy and aryloxy groups, and other atoms in various other groups.

Substituted alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl groups as well as other substituted groups also include groups in which one or more hydrogen bonds are replaced by one or more bonds, including double or triple bonds, to a carbon atom, or to a heteroatom, such as oxygen in (oxo)carbonyl, carboxyl, ester, amide, imide, urethane, and urea groups, and nitrogen in imines, hydroxyimines, oximes, hydrazones, amidines, guanidines and nitriles.

Substituted ring groups, such as substituted cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups also include rings and fused ring systems in which a bond to a hydrogen atom is replaced with a bond to a substituted alkyl, alkenyl, or alkynyl group as defined herein.

Suitable halogen substituents include fluorine, chlorine, bromine, and iodine, preferably fluorine.

The phrase ”(therapeutically) effective amount” as used herein is meant to refer to the amount of active compound that elicits the biological or medicinal response that is being sought in a tissue, system or subject by a researcher, veterinarian, medical doctor or other clinician (practitioner). The therapeutic effect is dependent upon the disorder being treated, the biological effect desired, or the clinical result desired.

As such, the therapeutic effect can be a decrease in the severity of symptoms associated with the disorder and/or inhibition (partial or complete; at least in part) of the progression of the disorder, or improved treatment, healing, prevention or elimination of a disorder, or side-effects.

The amount needed to elicit the therapeutic response can be determined, for example, based on the species, age, health, size, gender and/or sex of a subject.

Optimal amounts can also be determined based on monitoring of the subject’s response to treatment.

The terms “treatment” and “treating” as used herein are not meant to be limited to curing. Treating is meant to also include alleviating at least one symptom of a disease, removing at least one symptom of a disease, lessen at least one symptom of a disease, and/or delaying the course of a disease. The term “treatment” as used herein is also meant to include methods of therapy and diagnosis. Also, the terms are meant to include therapeutic treatment and prophylactic or preventative measures wherein the object 1s to prevent or slow down (lessen) an undesired physiological condition, disorder or disease, or obtain beneficial or desired clinical results.

Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of condition, disorder or disease, stabilized (i.e. not worsening) state of condition, disorder or disease, delay in onset or slowing of condition, disorder or disease progression, amelioration of the condition, disorder or disease state or remission (whether partial or total), whether detectable or undetectable, an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of condition, disorder or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. Thus, “treatment of a viral infection” or “treating a viral infection” means an activity that prevents, alleviates or ameliorates any of the symptoms associated with the specific viral infection and infectious diseases.

The phrase “treating a viral infection” or “treatment of a viral infection” also refers to the treatment of a subject infected with a virus that is capable of causing an infection or has already caused an infection. The treatment can (selectively) target virions.

The terms “virion” and “virus” as used herein are used interchangeably.

The terms “N-terminus” and “C-terminus” as used herein are meant to also include side chains or non-natural amino acids in the N- or C- terminal part (such as the terminal 4 or 3 amino acids) of the peptides.

The invention provides a compound, comprising at least two peptides that are physically linked through a linker, wherein each peptide comprises an amino acid sequence TFLDKFNHEAEDLFYQ or a variant thereof. In particular, each peptide is attached via its N-terminus and/or C-terminus to the linker.

The compound as described herein comprises at least two peptides having an amino acid sequence TFLDKFNHEAEDLFYQ or a variant thereof. In particular, the compound comprises 2 peptides, such as 3 or more, 4 or more, or 5 or more. Preferably, the compound comprises 2 or 3 peptides. More preferably, the compound comprises 3 peptides.

The compound may comprise two peptides, wherein both peptides are attached to the linker via their N-terminus; both peptides are attached to the linker via their C-terminus, or one peptide is attached to the linker via its N-terminus and the other peptide 1s attached to the linker via its C-terminus. In case the compound comprises three peptides, every peptide may be attached to the linker via their N-terminus; every peptide may be attached to the linker via their C-terminus; two peptides may be attached to the linker via their N-terminus and one peptide may be attached to the linker via its C-terminus, or two peptides may be attached to the linker via their C-terminus and one peptide may be attached to the linker via its N-terminus.

The peptides of the compound as described herein may be all isolated peptides, all synthetic, all recombinant peptides, or any combination of isolated, synthetic and recombinant peptides. For example, the compound may comprise one isolated peptide and two synthetic peptides. The peptides comprise at least an amino acid sequence TFLDKFNHEAEDLFYQ or a variant thereof. The peptides may comprise an amino acid sequence IEEQAKTFLDKFNHEAEDLFYQSSLA or a variant thereof.

The variant of the amino acid sequence may have at least 16 amino acids, preferably based on TFLDKFNHEAEDLFYQ, or at least 26 amino acids, preferably based on IEEQAKTFLDKFNHEAEDLFYQSSLA.

Either variant may further have one or more amino acids selected from L, I, V or A, substituted by another amino acid selected therefrom, one or more amino acids substituted by their corresponding D-amino acid, and/or one or more amino acids substituted by a corresponding non-natural amino acid.

In one embodiment one or more of the peptide further comprises one or more additional amino acids.

In one embodiment the additional amino acids comprise the sequence LGKGDFR (reflecting amino acid 351-357 of human ACE2 (Uniprot accession Q9BYF1). The additional LGKGDFR amino acids are preferably on the C-terminal side of the peptide, preferably associated with the peptide via a connector.

Examples of such peptides are described in Han et al. (2006, Virology 350: 15-25). The connector is preferably one or a short stretch of 2, 3 or 4 amino acids in peptide linkage with each other and the flanking amino acids.

In Han et al. (2006, Virology 350: 15-25) the connector is a glycine.

In peptides that are linked to the linker via their N-terminus, the connector is preferably one or two amino acid(s) in peptide linkage with the peptide and the additional LGKGDFR amino acids.

The one or two amino acid(s) are preferably one or two glycines, one or two beta-alanines or a combination of a glycine and a beta-alanine.

Peptides that comprise the additional LGKGDFR amino acids preferably have a sequence of at least the amino acids TFLDKFNHEAEDLFYQ preferably the amino acids IEEQAKTFLDKFNHEAEDLFYQSS.

In this last embodiment the connector is in peptide linkage with the C-terminal S and is preferably a glycine or a beta-alanine.

The connector amino acid is preferably in peptide linkage with the L of the additional LGKGDFR amino acids.

Non-limiting examples of suitable peptide-connector-additional LGHKGDFR amino acids peptides are IEEQAKTFLDKFNHEAEDLFYQSS-G-LGKGDFR; IEEQAKTFLDKFNHEAEDLFYQSS-betaA-LGKGDFR; and IEEQAKTFLDKFNHEAEDLFYQSS-GG-LGKGDFR, wherein betaA stands for beta-alanine and the “-* have no physical meaning but are indicated solely for illustrative purposes.

In peptides that are linked to the linker via their C-terminus, the connector is preferably one or two amino acid(s) in peptide linkage with the peptide and the additional LGKGDFR amino acids. The one or two amino acid(s) are preferably lysine and/or glycine. Peptides having the additional LGKGDFR amino acids that are linked to the linker via their C-terminus are preferably linked to the linker via a direct linkage of the linker to the connector. Non-limiting examples of suitable peptide-connector-additional LGHKGDFR amino acids peptides are IEEQAKTFLDKFNHEAEDLFYQSS-GL(PEG-SH)-LGKGDFR; and IEEQAKTFLDKFNHEAEDLFYQSS-L(PEG-SH)G-LGKGDFR wherein (PEG-SH) means a PEG-moiety attached to the lysine side-chain including a thiol modification for easy association with the linker.

A variant of the peptide TFLDKFNHEAEDLFYQ or IEEQAKTFLDKFNHEAEDLFYQSSLA preferably has up to 5 of the following amino acid substitutions: substitution of one or more amino acids selected from the group of L, I or A by another amino acid selected from L, I, V or A; substitution of one or more amino acids selected from the group of Kor H by an amino acid selected from R, Kor H; substitution of E by Q substitution of Y by F substitution of one or more amino acids selected from the group of Q.N, A, S or T by another amino acid selected from said group;

having one or more substitutions of an amino acid by a corresponding D-amino acid, having up to 5 substitutions of an amino acid by a corresponding non-natural amino acid, and/or having a retro-inverso sequence of at least 16 consecutive amino acids from said amino acid sequence.

A variant of the peptide TFLDKFNHEAEDLFYQ such as IEEQAKTFLDKFNHEAEDLFYQSSLA preferably has up to 5 of the following amino acid substitutions: substitution of one or more amino acids selected from the group of L, I or A by another amino acid selected from L, I, V or A; substitution of one or more amino acids selected from the group of K or H by an amino acid selected from R, K or H; substitution of E by Q substitution of Y by F substitution of one or more amino acids selected from the group of Q, N, A, S or T by another amino acid selected from said group; having one or more substitutions of an amino acid by a corresponding D-amino acid, having up to 5 substitutions of an amino acid by a corresponding non-natural amino acid, and/or having a retro-inverso sequence of at least 16 consecutive amino acids from said amino acid sequence.

Variants of the peptides TFLDKFNHEAEDLFYQ or TEEQAKTFLDKFNHEAEDLFYQSSLA preferably have 1, 2, 3 or 4 of the described amino acid substitutions. Preferably a variant has 1, 2 or 3 of the described amino acid substitutions, more preferably 1 or 2, more preferably 1 of the described amino acid substitutions.

Variants of the peptide TFLDKFNHEAEDLFYQ that are 16-26 amino acids long preferably have a consecutive sequence of the peptide

IEEQAKTFLDKFNHEAEDLFYQSSLA, or a variant having up to 1, 2, 3 or 4 of the described amino acid substitutions.

A variant of peptide or amino acid sequence TFLDKFNHEAEDLFYQ or IEEQAKTFLDKFNHEAEDLFYQSSLA as defined herein may comprise up to 5 substitutions of an amino acid by a corresponding non-natural amino acid. “Non-natural amino acids” as used herein refers non-genetically encoded amino acids, irrespective of whether they appear in nature or not.

Non-natural amino acids that can be present in a variant of an amino acid sequence as defined herein include: beta-amino acids; p-acyl-L-phenylalanine; N-acetyl lysine; O-4-allyl-L-tyrosine; 2-aminoadipic acid; 3-aminoadipic acid; beta-alanine; 4-tert-butyl hydrogen 2-azidosuccinate; beta-aminopropionic acid; 2-aminobutyric acid; 4-aminobutyric acid; 2, 4,-diamino butyric acid; 6-aminocaproic acid; 2-aminoheptanoic acid; 2-aminoisobutyric acid; 3-aminoisobutyric acid;

2-aminopimelic acid; p-aminophenylalanine; 2,3-diaminobutyric acid; 2,3-diamino propionic acid; 2,2'-diaminopimelic acid; p-amino-L-phenylalanine; p-azido-L-phenylalanine; D-allylglycine; p-benzoyl-L-phenylalanine; 3-benzothienyl alanine p-bromophenylalanine; t-butylalanine; t-butylglycine; 4-chlorophenylalanine; cyclohexylalanine;

cysteic acid; D-citrulline; thio-L-citrulline; desmosine; epsilon-amino hexanoic acid; N-ethylglycine; N-ethylasparagine; 2-fluorophenylalanine; 3-fluorophenylalanine; 4-fluorophenylalanine; homoarginine; homocysteine; homoserine; hydroxylysine; allo-hydroxylysine; 3-(3-methyl-4-nitrobenzyl)-L-histidine methyl ester; isodesmosine;

allo-isoleucine; isopropyl-L-phenylalanine; 3-methyl-phenylalanine; N-methylglycine; N-methylisoleucine; 6-N-methyllysine; O-methyl-L-tyrosine; N-methylvaline; methionin sulfoxide; 2-napthylalanine; L-3-(2-naphthyl)alanine; isoserine; 3-phenylserine; norvaline; norleucine; 5,5,5-trifluoro-DL-leucine; ornithine;

3-chloro-tyrosine; N5-carbamoylornithine; penicillamine; phenylglycine;

piperidinic acid; pyridylalanine; 1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid; beta-2-thienylalanine; y-carboxy-DL-glutamic acid; 4-fluoro-DL-glutamic acid; D-thyroxine; allo-threonine; 5-hydroxy-tryptophan; 5-methoxy-tryptophan; 5-fluoro-tryptophan; 3-fluoro-valine.

In one embodiment, a natural amino acid of said sequence is substituted by a corresponding non-natural amino acid. As used herein, a “corresponding non-natural amino acid” refers to a non-natural amino acid that is a derivative of the reference natural amino acid. For instance, a natural amino acid is substituted by the corresponding beta-amino acid. Beta-amino acids have their amino group bonded to the beta carbon rather than the alpha carbon as in the natural amino acids. Examples of substitution of a natural amino acid by a non-natural amino acid that is a derivative of said natural amino acid are the following. Alanine is for instance substituted by beta-alanine, t-butylalanme, 2-napthylalanine; L-3-(2-naphthyDalanine, 2-aminoisobutyric acid. Arginine is for instance substituted by homoarginine, ornithine, N5-carbamoylornithine, 3-amino-propionic acid. Asparagine is for instance substituted by N-ethylasparagine. Aspartic acid is for instance substituted by 4-tert-butyl hydrogen 2-azidosuccinate. Cysteine is for instance substituted by cysteic acid, homocysteine. Glutamic acid is for instance substituted by y-carboxy-DL-glutamic acid; 4-fluoro-DL-glutamic acid. Glutamine is for instance substituted by D-citrulline, thio-L-citrulline. Glycine is for instance substituted by N-methylglycine, t-butylglycine, N-methylglycine, D-allylglycine. Histidine is for instance substituted by 3-(3-methyl-4-nitrobenzyl)-L-histidine methyl ester. Isoleucine is for instance substituted by isodesmosine, N-methylisoleucine, allo-isoleucine. Leucine is for instance substituted by norleucine, desmosine, 5,5,5-trifluoro-leucine. Lysine is for instance substituted by 6-N-methyllysine, 2-aminoheptanoic acid, N-acetyl lysine, hydroxylysine,

allo-hydroxylysine. Methionine is for instance substituted by methionin sulfoxide. Phenylalanine is for instance substituted by p-amino-L-phenylalanine, 3-benzothienyl alanine p-bromophenylalanine, p-acyl-L-phenylalanine, 2-fluorophenylalanine, 3- fluorophenylalanine, 4-fluorophenylalanine. Proline is for instance substituted by 3-hydroxyproline, 4-hydroxyproline, 1-acetyl-4-hydroxy-L-proline. Serine is for instance substituted by homoserine, isoserine, 3-phenylserine. Threonine is for instance substituted by D-thyroxine, allo-threonine. Tryptophan is for instance substituted by 5-hydroxy-tryptophan, 5-methoxy-tryptophan, 5-fluoro-tryptophan. Tyrosine is for instance substituted by O-methyl-L-tyrosine, O-4-allyl-L-tyrosine, 3-chloro-tyrosine. Valine is for instance substituted by norvaline, N-methylvaline, 3-fluoro-valine.

In amino acid sequences or variants thereof as defined herein amino acids are denoted by single-letter symbols. These single-letter symbols and three-letter symbols are well known to the person skilled in the art and have the following meaning: A (Ala) is alanine, C (Cys) is cysteine, D (Asp) 1s aspartic acid, E (Glu) 1s glutamic acid, F (Phe) is phenylalanine, G (Gly) 1s glycine, H (His) is histidine, I (Ile) is isoleucine, K (Lys) is lysine, L (Leu) 1s leucine, M (Met) is methionine, N (Asn) is asparagine, P (Pro) is proline, Q (Gln) is glutamine, R (Arg) is arginine, S (Ser) is serine, T (Thr) is threonine, V (Val) 1s valine, W (Trp) 1s tryptophan, Y (Tyr) is tyrosine.

A peptide of the invention may comprise non-peptidic structural elements. Such non-peptidic structural elements may be present in the amino acid sequence TFLDKFNHEAEDLFYQ), TEEQAKTFLDKFNHEAEDLFYQSSLA, or in a variant thereof as defined herein, as a result of substitution of modification of one or more amino acids of said sequence or variant. Alternatively, a peptide of the invention may comprise non-peptidic structural elements outside the amino acid sequence TFLDKFNHEAEDLFYQ or IEEQAKTFLDKFNHEAEDLFYQSSLA or in a variant thereof as defined herein, i.e. in the optional N- and/or C-terminal elongating groups. A non-peptidic structural element is typically a modification of one or more existing amino acids. Preferred peptidomimetics are obtained by structural modification of a peptide as described herein, for instance using non-natural amino acids such as defined herein above, conformational restraints, cyclization of the polypeptide, isosteric replacement or other modifications. The amino acid sequence of a peptide according to the invention thus optionally comprises one or more modifications. Such peptide may be modified by natural processes, such as posttranslational processing, or by chemical modification techniques.

Modifications may be inserted at any location in said peptide, including in the peptide backbone, amino acid side-chains and at the N- or C-terminus. A single peptide may contain multiple types of modifications or several modification of a single type. Modifications include acetylation, amidation, acylation, phosphorylation, methylation, demethylation, ADP-ribosylation, disulfide bond formation, ubiquitination, gamma-carboxylation, glycosylation, hydroxylation, iodination, oxidation, pegylation and sulfation. In addition a peptide as described herein may be provided with a label, such as biotin, fluorescein or flavin, a lipid or lipid derivative, a sugar group.

The alpha-helical character of the peptides may be increased and/or stabilized by introducing one or more intramolecular crosslinks. The o-helix features 3.6 residues per complete turn, which places side chains at positions i, i+4, and i+7 on the same face of the folded structure. Preferably, the alpha-helical conformation in peptides employs one or more crosslinks between amino acids at positions z and z+4 or z and +7. Amino acid positions suitable for crosslinks between the z and i+4 side chain groups include 21/25, 22/26, 25/29, 28/32, 29/33, 32/36, 36/40, 39/43, and 40/44. Amino acid positions suitable for crosslinks between the i and +7 side chain groups include 21/28, 22/29, 25/32, 26/33, 29/36, 32/39, 33/40, 36/43, and 39/46. Well-known side chain crosslinks used for stabilizing peptide alpha-helices can be obtained via lactamization, thioether formation, click reactions and metathesis. Each of these can be employed in the present invention. Some illustrative examples are shown in Figure 1.

The compound as described herein comprises a linker which may comprise any of a trivalent atom, preferably a trivalent atom, such as nitrogen, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl.

The compound as described herein may be a compound of formula (D or (II), wherein the formulas are DI), ma ERR wherein m and n are, independently, integers of 1-100; 01s at least 1; V and Y are spacers, independently, derived from amino acids, amino thioacids, diprotic acids, such as dicarboxylic acids and dithiocarboxylic acids, diols, such as glycols, and/or mercapto alcohols; Wis - a multivalent atom, preferably a trivalent atom, such as nitrogen, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted linear or branched alkenyl, optionally substituted linear or branched heteroalkenyl, optionally substituted linear or branched alkynyl, optionally substituted linear or branched heteroalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl; or - CR3 or SiR?, wherein R3 hydrogen or a label, such as a PEG label, a fluorescent label, an isotope, or a bio-orthogonal handle; X is optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted linear or branched alkenyl, optionally substituted linear or branched heteroalkenyl, optionally substituted linear or branched alkynyl, optionally substituted linear or branched heteroalkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl; and Z 1s a peptide as described herein, wherein Z is attached to Vor Y via N-terminus and/or C-terminus.

Preferably, “m” and “n” in formula (I) or (II) are, independently, integers of 2-10, such as 2, 4 or 6. Preferably, “0” in formula (I) is 2 or 3, and more preferably 3.

The V and Y in formula (I) or (II) may be, independently, derived from amino acids and/or diols. In particular, the V and Y are, independently, derived from diols, such as linear diols, e.g., ethylene glycol, linear amino acids, such as 4-aminobutyric acid, 5-aminovaleric acid and 6-amino-hexanoic acid, a-amino acids and/or B-amino acids selected from arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, selenocysteine, glycine, proline, alanine, valine, isoleucine, leucine, methionine, phenylalanine, ornithine, tyrosine, tryptophan, and derivatives thereof. Preferably, V and Y are, independently, glycine, serine and/or ethylene glycol.

The compound as described herein may have any of the following formulas:

z Er AEN { he “Bw Xx Bw DN NI x x 1, 1, DV], z (Ia), z (Ta-H), z (Ib), z A Nx VIX 2 " \ Hx { \ d= Ii N X ” Se] MI, z (Ib-H), z (Ic),

A LY] z Xx x] 9 ” Saga z—fy m= + i (Ic-H-0), 1, ° (Ic-H-m), 72 =, (Te-Hop), wherein X comprises —(CH2)2:NHC(=0)CH:—, —-CH2NHC(=0)(CH2)2—, -CH:NHC@=0)CH--, —(CH2)2NHC(=0)(CH3)2—, —C(=0)CH:2NHC(=0)CH.—, —C(=0)CH3z—, —C(=0)(CHs)2—, -NHS(=0)2(CH3)s—, -NHS(=0)2CH2—, —(CH2):NHS(=0)2(CHz)2—, -CH:NHS(=0)4(CHs)2-, -(CH;)2NHS(=0):CHa-, -CH:NHS(=0):CH:-, -C@=0)CH:NHS(=0):CH:-, —C(=0)CH:NHS(=0)2(CHz)2—, -C=0)(CH2):NHS(=0)2CHs-, -C=0)(CH;)2NHS(=0})2(CH>)2-, -S=0)2CHs-, -CHsS(=0)2CHs-, -S(=0)2(CH>):-, -CH:58=0)24(CH2)2-, —(CH2)2S(=0)2(CHe)2—, —(CH3)2:NHC(=0)(CH)2CHgz—, —CH2NHC(=0)(CH)2(CHz)2—,

—(CHy):NHC(=0)(CH)2(CHs)2—, -CH2NHC(=0)(CH)2:CH2—, —C(=0)CH:2NHC(=0)(CH)2CH2—, —C(=0)CH:2NHC(E=0O)CH)2(CHz)2—, -CEO)CH>):NHCEO)CH):CH:, —C(=0)(CH2)2NHC(=0)(CH)2(CHz)2—, —C(=0)(CH):CH2—, —C(=0)(CH)2(CHzy)2—, -NHP=OXOR)(CH:)2-, -NHPEO)XOR)(CCH):-, -NHC(=0)(CH)2CHz—, -NHC(=0)(CH)2(CHy)2—, Dee ASSN <A, -NHC@O)N=S(CH;)-, -C=O)NH-, NN optionally RE ho N== A += I Ny 8 wy No substituted * , Ä — NA Ro or derivatives thereof, wherein R'is alkyl, cycloalkyl or aryl, and R71s hydrogen, alkyl, cycloalkyl or aryl; Wis N, CR? or SiR3; R3 is hydrogen or a label, such as a PEG label, a fluorescent label, an isotope, or a bio-orthogonal handle; and QisCH or N or wherein the compound has one of the following formulas: se Oc nz (a) or z A A z my pik Ny a, wherein n is an integer of 1-100, preferably 2-10; L is amino acid, preferably glycine and/or serine, and A comprises -NHC(=0)CHsz-, -CHsNHC{=0)-, -CH:NHC{=0)CH:, -CH:NHCEO)(CHs):-, -(CH>2NHC(=0)CH:-, —(CH3z)2NHC(=0)(CHg)2—, -CHCHeNHC(=0)CH:-, -CH:sNHC(=0)CH:CH-,

—CH:NHC(E=0)(CH2)2:CH—, -CH(CH2):NHC(=0)CH:—, 0 Sx “IN / —CH(CHg2):NHC(=0)(CHz)>—, © , or derivatives thereof; m is an integer of 1-100, preferably 2-10; Y is a spacer, preferably derived from amino acids, amino thioacids, diprotic acids, such as dicarboxylic acids and dithiocarboxylie acids, diols, such as glycols, and/or mercapto alcohols, and Z is a peptide as described herein.

The compound as described herein may have any of the following formulas: 9 0 NH-Z 8 Io.

Y wi fo N Rh 2 2 A So SET woo Ly o 9 3 o Ao NE Po AS 0 3 (Id-C1), ? o Nez nA Ao o | = 1 oO o N O- ; | o Ax ~~ 1 o So _ ~~ PR 3 Sy z wo DNH o (Id-C2),

1 0 cor? Nhe oP} 3 0 NN he

NN TN N— Ln o 4 / LN er 0h VZ on 4 3 NE Po NH ~cor* 0 3 (Id-C3), o o | i s7 ef do zoo oy 3 o o il 4 NN fF oH zon oy 7 Î eo 3 1 i Ak dn zoo" (Id-N1), o 0 i ak zoon ox N= and Oo ~0 Sd ho 0 o = © ay 5 (Id-N2), or oo , 0 Oo nzo! HN 32 9 Nez / I “Gon “NH-Z-coRr* N NH 5 ie / 7°

N FN

A ¢N N-N La ee nez-cort “Lo 5 (Id-N3), wherein Z is as defined above, and each R4 is independently OH or NH:.

There is also provided herein a pharmaceutical composition comprising a compound as described herein.

In an embodiment, the pharmaceutical composition comprises one or more compounds of formula (I) or (IT) as described herein, for example, one or more compounds of any of formulas Ia, Ia-H, Ib, Ib-H, Ie, Ic-H-o, Ic-H-m, Ic-H-p, Ila, Ib, Id-C1, Id-C2, Id-C3, Id-N1, Id-N2, or Id-N3.

The compound as described herein, including the compounds according to any of the formulas depicted herein, and the pharmaceutical composition as described herein, may be used in medical applications, such asin medicine, for example, as a medicament, such as a pharmaceutical.

The compound as described herein may be used for treating a medical disorder (i.e., a disease, condition or symptom(s)), especially coronavirus infections. The compound and the pharmaceutical composition as described herein may be for use in the prevention or treatment of a viral infection, such as an infection caused by coronavirus.

In particular, the coronavirus as described herein utilizes the ACE2 receptor for entry into a cell. Coronaviruses, such as SARS-CoV and SARS-CoV-2 initiate entry into human cells by targeting ACE2 which forms a heterotetrameric transmembrane complex with BVAT1. It is believed that the virus protein responsible for this interaction is the spike protein (S- protein) which binds ACE2 via its receptor binding domain (RBD). The S- proteins of inter alia abovementioned coronaviruses are homologous and target the analogous site on ACE2. The entry-process is central to the virulence of coronaviruses. Hence, the inventors designed high-affinity compounds as described herein that bind to the RBD of the S-protein thereby inhibiting the interaction between the virion and the human host cell. The S-protein is exposed on the outside of the viral capsid. The RBD adopts two possible conformations with the S-proteins, i.e., closed or open (Figure 2). Further analysis led the inventors to believe that additional conformations can be expected, such as two-open and all-open conformations

(Figure 2D). Coronavirus binds to ACE2 via the RBD of the S-protein. A CryoEM structure of the complex between the B9AT1-ACE2 receptor and the RBD was reported in the art (Figure 2B). The structure reveals an o- helix in ACE2 that is believed to mediate most of the contacts with the RBD. The helical ACE2-derived interaction motif comprises 26 amino acids (IEEQAKTFLDKFNHEAEDLFYQSSLA) (Figure 2C). Overlaying the RBD bound to the ACE2-derived helix with the closed or all-open S-protein structures provides two distinct helix orientations for either conformation. For the open conformation the helix C-termini point towards each other, while for the closed conformation the N-termini point towards each other. Based on the above surprising observation, the inventors designed the herein described compound as suitable spike protein-targeting peptide- based inhibitors of which the C-terminal linked peptides target the closed conformation, whereas the N-terminal linked peptides target the all- or partially open conformations.

The coronavirus as described herein may be any coronavirus, such as a betacoronavirus. Preferably, the coronavirus is a severe acute respiratory syndrome-related coronavirus or a Middle East respiratory syndrome-related coronavirus. More preferably, the coronavirus is SARS-CoV, SARS-CoV-2 or MERS-CoV. In a particularly preferred embodiment the coronavirus is SARS-CoV or SARS-CoV-2, preferably SARS-CoV-2. Viral infections, such as coronavirus infection, as described herein, may refer to an infection in any part of the individual's (body), in particular the respiratory and gastrointestinal tracts or part(s) thereof.

A medical use or medical method of a compound as described herein is preferably a use or method for the treatment of an individual that is infected or suspected of being infected by a virus that can enter a cell via the ACE2 receptor (not excluding additional target receptors). In a preferred embodiment the virus is a coronavirus, preferably a severe acute respiratory syndrome-related coronavirus or a Middle East respiratory syndrome-related coronavirus. More preferably, the coronavirus is SARS-CoV, SARS-CoV-2 or MERS-CoV. In a particularly preferred embodiment the coronavirus is SARS-CoV or SARS-CoV-2, preferably SARS-CoV-2. Viral infections, such as coronavirus infection, as described herein, may refer to an infection in any part of the individual's (body), in particular the respiratory and gastrointestinal tracts or part(s) thereof.

In an embodiment, the compound provided by the invention is used in a method of therapy and/or (in vivo) diagnostics. The method of therapy and/or (in vivo) diagnostics is a method of detecting and/or treating a viral infection, particularly in the treatment of one or more viral infections caused by virulent virions, such as coronavirus. The compound may be used in the preparation of a medicament for detecting and/or treating a viral infection, particularly for treating one or more viral infections caused by virulent virions, such as coronavirus. Any other known medicament, compound, or composition used for the treatment of a viral infection can be used in co-therapy, co-administration or co-formulation with the compound.

In another embodiment, the compound provided by the invention 1s used for the manufacture of a medicament, such as a medicament for therapy and/or (in vivo) diagnostics. In particular, the compound as described herein is used for the manufacture of a medicament for the treatment of one or more viral infections caused by coronavirus. Preferably, the compound is used for the manufacture of a medicament for the treatment of viral infections caused by virulent virions, such as coronavirus.

There is also provided the compound provided by the invention for use in the prevention or treatment of a viral infection, comprising administering to a subject in need thereof the compound. The administering of the compound may be performed for a time sufficient to treat the viral infection. In particular, the viral infection may be caused by a virulent coronavirus, such as a severe acute respiratory syndrome-related coronavirus or a Middle East respiratory syndrome-related coronavirus. The compound may be used to treat a viral infection, comprising administering to a subject, preferably a subject in need thereof, the compound.

There are also provided methods of treating viral infections. In an embodiment, the method comprises administering to a subject with a viral infection, or a subject suspected of having a viral infection the compound according to the invention. In particular, the subject is in need of treatment of coronavirus infection(s), such as severe acute respiratory syndrome-related coronavirus infection or Middle East respiratory syndrome-related coronavirus infection. The treatment of viral infections can be targeted against virions and/or virus. In particular, the compound selectively targets virions.

There is further provided a method for inhibiting infection of a cell that is permissive for coronavirus, comprising: - providing the cell with a compound as described herein or a pharmaceutical composition as described herein.

In particular, the cell is provided with a therapeutic effective amount of the compound or pharmaceutical composition. The cell preferably expresses a receptor for the coronavirus. In one embodiment the receptor is the ACE2 virus receptor. A coronavirus such as the SARS-CoV-2 has been shown to enter cells that do not express ACE2. Such infections are also thought to be dependent on the spike protein. A compound as described herein because of the interaction with the spike protein may also inhibit such infections. There is further provided a method for treating an infection caused by coronavirus in an individual, comprising: - administering a compound as described herein or a pharmaceutical composition as described herein. In particular, the individual is in need for treatment of coronavirus infection.

There is further provided a method for treating an infection caused by a virus that can enter a cell via the ACE2 receptor, preferably a coronavirus in an individual, comprising:

- administering a compound as described herein or a pharmaceutical composition as described herein. In particular, the individual is in need for treatment of coronavirus infection.

In a further embodiment, the compound according to the invention is for use in the diagnosis of a disease caused by a virus, especially virulent coronavirus, such as severe acute respiratory syndrome-related coronavirus or Middle East respiratory syndrome-related coronavirus. The compound may be used in the preparation of a medicament for diagnosing a coronavirus disease, such as COVID-19.

In another embodiment, a method is provided of diagnosing a disease in a subject, comprising administering to the subject the compound according to the invention. In particular, the disease may be caused by a virulent coronavirus, such as a severe acute respiratory syndrome-related coronavirus or Middle East respiratory syndrome-related coronavirus.

In another embodiment, the compound according to the invention is used, preferably as medicament, in (a method for) the treatment of an individual. The compound may be used in the manufacture of a medicament for the treatment of an individual.

The compounds as described herein may be administered in any conventional manner by any route where the compound is active or becomes active. Administration can be systemic, topical or oral. Preferably, the administration is by one or more of depot injection, nebulization/inhalation, intravenous, and subcutaneous. The modus of administration may depend on the conditions or disease to be targeted or treated. The selection of the specific route of administration can be selected or adjusted by the clinician according to methods known to the clinician to obtain the desired clinical response. It may be desirable to administer one or more of the compounds locally to an area suitable for treatment, such as an area in need of treatment.

The compound as described herein may be administered either alone or in combination (concurrently or serially) with other compounds, such as pharmaceutically acceptable compounds and/or prodrugs. For example, the compound may be administered in combination with other analgesics, antidepressants, anti-anxiety compounds, anti-overactive bladder compounds, antibiotics, and/or compounds for the treatment of coronavirus infections.

The amount of compound as described herein to be administered is that amount which is therapeutically effective. The dosage to be administered will depend on the characteristics of the individual being treated, e.g., the particular species treated, age, weight, health, types of concurrent treatment, if any, and frequency of treatments, and can be easily determined by, e.g., a clinician. The dosage of the compounds as described herein can be used and adjusted depending upon the factors above. The selection of the specific dose regimen can be selected or adjusted or titrated by a clinician according to methods known in the art to obtain the desired clinical response.

The amount of the compound as described herein that will be effective in the treatment and/or prevention of a particular disease, condition or disorder, will depend on the nature and extent of the disease, condition or disorder, and can be determined by standard clinical techniques. In addition, e.g., in vitro or in vivo assays may optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the compositions will also depend on the route of administration, and the seriousness of the disorder, and should be decided according to the judgment of the practitioner and the patient's condition(s). Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems (animal models).

The compound as described herein can be formulated for parenteral administration by injection. Formulations for injection can be presented in unit dosage form, such as in ampoules or in multi-dose containers, with an optionally added preservative or stabilizing agent. The compounds can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents, such as suspending, stabilizing and/or dispersing agents. In some embodiments, the injectable is in the form of a short-acting, depot or implant. In some embodiments, the parenteral dosage form is the form of a solution, suspension, emulsion, or dry powder.

For oral administration, the compound as described herein can be formulated by combining the compounds with pharmaceutically acceptable carriers. Such carriers enable the compounds to be formulated, for example, as tablets, pills, dragées, capsules, emulsions, liquids, gels, syrups, caches, pellets, powders, granules, slurries, lozenges, aqueous or oily suspensions, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by, for example, adding a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragées. Suitable excipients include, but are not limited to, fillers such as sugars, including, but not limited to, lactose, sucrose, mannitol, and sorbitol; cellulose preparations such as, but not limited to, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and polyvinyl pyrrolidone. If desired, disintegrating agents can be added, such as, but not limited to, the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.

Orally administered compositions can contain one or more optional agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents, such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation. Moreover, where in tablet or pill form, the compositions may be coated to delay disintegration and absorption in the gastrointestinal tract thereby providing a sustained action over an extended period of time.

Selectively permeable membranes surrounding an osmotically active driving compound are also suitable for orally administered compounds.

Oral compositions can include standard vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc.

Such vehicles are suitably of pharmaceutical grade.

Dragées can be provided with suitable coatings.

For this purpose, concentrated sugar solutions can be used, which can optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.

Dyestuffs or pigments can be added to the tablets or dragée coatings for identification or to characterize different combinations of active compound doses.

Pharmaceutical preparations which can be used orally include, but are not limited to, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.

The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.

In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.

In addition, stabilizers can be added.

For buccal administration, the compositions can take the form of, such as, tablets or lozenges formulated in a conventional manner.

For administration by inhalation, the compounds as described herein can be delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.

In the case of a pressurized aerosol the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, such as gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

The compound according to the invention can be present in a cream, solution, powder, fluid emulsion, fluid suspension, semi-solid, ointment, paste, gel, jelly, and foam, or in a patch containing any of the same. The compound can be formulated as a depot preparation. Such long acting formulations can be administered by implantation or by injection.

Thus, for example, the compound can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. The compound can be contained in formulations with pharmaceutically acceptable diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, preservatives or the like.

The pharmaceutical composition as described herein can comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

In some embodiments, the compound according to the invention is used with agents, such as topical analgesics, barrier devices, or rinses. In other embodiments, the compound is delivered in a vesicle, in particular a liposome.

In some embodiments, the compound according to the invention is lyophilized to a solid and reconstituted with, for example, water prior to use. When administered to a mammal (e.g., to an animal for veterinary use or to a human for clinical use) the compound can be administered in isolated form. When administered to a human, the compound can be sterile. Water is a suitable carrier when the compound is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical carriers also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, tale, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, dimethyl sulfoxide, and ethanol. Compositions comprising the compound, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.

The compound as described herein and/or compositions containing the compound can take the form of a solution, suspension, emulsion, tablet, pill, pellet, capsule, capsule containing a liquid, powder, sustained-release formulation, suppository, aerosol, spray, or any other form suitable for use.

In some embodiments, the compound according to the invention is formulated in accordance with routine procedures as a pharmaceutical composition adapted for administration to, in particular humans. Typically, the compound can be in the form of a solution in a sterile isotonic aqueous buffer. Where necessary, the composition can also include a solubilizing agent. Compositions for intravenous administration may optionally include a local anesthetic such as lidocaine to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampule or sachets indicating the quantity of active agent. Where the compound is to be administered by infusion, it can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the compound is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.

The compounds and (pharmaceutical) compositions, comprising a compound as described herein, can be in unit dosage form. In such form, the compound can be divided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparations, for example, packeted tablets, capsules, and powders in vials or ampules. The unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms.

In some embodiments, a composition comprising the compound according to the invention is in the form of a liquid wherein the active agent 1s the compound. For example, the compound may be present in solution, 1n suspension, as an emulsion, or as a solution/suspension. The liquid composition may be in the form of a gel. The liquid composition may be aqueous. The composition may be in the form of an ointment.

In an embodiment, an isotope carrier is provided comprising the compound according to the invention, wherein the compound comprises one or more stable nuclides. The isotope carrier may be suitable for diagnostics in that the presence of the isotope carrier can be detected, for example, when used in vivo. Suitable stable nuclides include deuterium, 13C, 15N, 83S, MS, 36S, 170, and 180.

In an embodiment, a pharmaceutical kit is provided comprising one or more containers filled with one or more compounds according to the invention. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration for treating a condition, disease, or disorder described herein, preferably coronavirus infection. In some embodiments, the kit contains more than one compound as described herein.

In some embodiments, the individual compounds as depicted herein are provided. These compounds may be used in medical applications, such as in medicine. The compounds may be used for treating medical disorders (z.e., diseases, conditions or symptom s)), especially coronavirus disease, such as COVID-19. The compounds may be used in any method as described herein, such as a method of therapy and/or (in vivo) diagnostics, in particular to detect and/or treat viral infection, especially in the treatment of one or more viral infections caused by virulent coronaviruses, such as SARS-CoV, SARS-CoV-2 or MERS-CoV.

The invention has been described by reference to various embodiments, and methods. The skilled person understands that features of various embodiments and methods can be combined with each other.

All references cited herein are hereby completely incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

The use of the terms “a” and “an” and “the” and similar referents in the context of describing the invention (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms “comprising”, “having”, “including” and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to”) unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention. For the purpose of the description and of the appended claims, except where otherwise indicated, all numbers expressing amounts, quantities, percentages, and so forth, are to be understood as being modified in all instances by the term “about”. Also, all ranges include any combination of the maximum and minimum points disclosed and include any intermediate ranges therein, which may or may not be specifically enumerated herein. Preferred embodiments of this invention are described herein.

Variation of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject-matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context. The claims are to be construed to include alternative embodiments to the extent permitted by the prior art.

For the purpose of clarity and a concise description features are described herein as part of the same or separate embodiments, however, it will be appreciated that the scope of the invention may include embodiments having combinations of all or some of the features described. The invention will now be further illustrated by the following non-limiting examples.

Examples Example 1 - Synthesis of Id-C1, Id-N1 All solvents used were degassed before use by purging the solvents with argon for 30 min.

To an ammonium carbonate buffer solution (20 mM, pH 7.9) was added 0.5 mM of 1,1',1"-(1,3,5-tr1azinane-1,3,5-triyDtrzs(2-bromoethanone) (TATB, 125 ul, 2 mM in MeCN) and 4 mM of the respective thiol-peptide (200 nl, 10 mM in water) which resulted in a MeCN : buffer solution (1: 3, 500 pl). The mixture was incubated for 2 h at 25 °C and 600 rpm.

After reaching full conversion, the product was purified by means of A) SulfoLink Coupling resin under reductive conditions, and/or B) preparative reversed phase HPLC using a gradient of MeCN and H:0 (0.1 % TFA). Example 2 - Synthesis of Id-C2, Id-N2 All solvents used were degassed before used by purging the solvents with argon for 30 min.

A solution of 1 mM of 1,11-bismaleimido-triethyleneglycol (2 ul at 5 mM in DMSO) and 2.1 mM of the respective thiol-peptide (0.9 ul, 20 mM in water) in PBS (pH 7.4) was incubated for 3 h at 25 °C and 600 rpm.

After reaching full conversion, the product was purified by means of A) SulfoLink Coupling resin under reductive conditions, and/or B) preparative reversed phase HPLC using a gradient of MeCN and H20 (0.1 % TFA). Example 2 - Synthesis of Id-C3, Id-N3 The respective azide-peptide was dissolved in DMF / H:0 (2 : 1, 4 mM) and to this 1 mM tripropargylamine (100 mM in DMF) was added.

To this was added a pre-incubated mixture of CuSO4 (6 mM), THPTA-ligand (6 mM) and sodium ascorbate (30 mM) in H2O was added.

After full completion of the reaction 30 mM EDTA-solution was added (0.1 M in water). The mixture was purified by preparative reversed phase HPLC using a gradient of MeCN and HsO (0.1 % TFA).

As an illustrative example for each of the synthesis examples, Figure 3 shows the characterization of Id-N2 (C-terminal acid, R+= OH).

Figure 3A shows the HPLC chromatogram of Id-N2. Eluent a is water, eluent b is acetonitrile (each with 1 % formic acid and 0.01 % trifluoroacetic acid). The eluent used for the HPLC corresponds to 0-2 min 5 % of eluent a and 95 % eluent b, followed by 2-6 min linear gradient 5 % to 95% of eluent a and 95 % to 5 % eluent b.

Figure 3B shows an electrospray ionization mass spectrometry (ESI MS) spectrum with calculated signals: 812 (9+), 914 (8+), 1044 (7+), 1218 (6+), 1461 (5+), 1827 (4+).

2025303SEQcdrom (2)

SEQUENCE LISTING <110> Stichting VU <120> CORONAVIRUS TARGETING DRUGS <130> P126846NL00 <140> NL 2025303 <141> 2020-04-08 <160> 9 <170> PatentIn version 3.5 <210> 1 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 1 Thr Phe Leu Asp Lys Phe Asn His Glu Ala Glu Asp Leu Phe Tyr Gln 1 5 10 15 <210> 2 <211> 26 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 2 Ile Glu Glu Gln Ala Lys Thr Phe Leu Asp Lys Phe Asn His Glu Ala 1 5 10 15 Glu Asp Leu Phe Tyr Gln Ser Ser Leu Ala <210> 3 <211> 7 <212> PRT <213> Homo sapiens Pagina 1

2025303SEQcdrom (2) <400> 3 Leu Gly Lys Gly Asp Phe Arg 1 5 <210> 4 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 4 Leu Gly His Lys Gly Asp Phe Arg 1 5 <210> 5 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 5 Ile Glu Glu Gln Ala Lys Thr Phe Leu Asp Lys Phe Asn His Glu Ala 1 5 10 15 Glu Asp Leu Phe Tyr Gln Ser Ser Gly Leu Gly Lys Gly Asp Phe Arg

<210> 6 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> peptide <220> <221> MOD_RES <222> (25)..(25) <223> bAla Pagina 2

2025303SEQcdrom (2) <400> 6 Ile Glu Glu Gln Ala Lys Thr Phe Leu Asp Lys Phe Asn His Glu Ala 1 5 10 15 Glu Asp Leu Phe Tyr Gln Ser Ser Ala Leu Gly Lys Gly Asp Phe Arg

<210> 7 <211> 33 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 7 Ile Glu Glu Gln Ala Lys Thr Phe Leu Asp Lys Phe Asn His Glu Ala 1 5 10 15 Glu Asp Leu Phe Tyr Gln Ser Ser Gly Gly Leu Gly Lys Gly Asp Phe 20 25 30 Arg <2105 8 <211> 33 <212> PRT <213> Artificial Sequence <220> <223> peptide <220> <221> MOD_RES <222> (26)..(26) <223> lysine with PEG moiety attached to side chain, including thiol modification <400> 8 Ile Glu Glu Gln Ala Lys Thr Phe Leu Asp Lys Phe Asn His Glu Ala 1 5 10 15 Pagina 3

2025303SEQcdrom (2) Glu Asp Leu Phe Tyr Gln Ser Ser Gly Xaa Leu Gly Lys Gly Asp Phe

Arg <216> 9 <211> 33 <212> PRT <213> Artificial Sequence <220> <223> peptide <220> <221> MOD_RES <222> (25)..(25) <223> lysine with PEG moiety attached to side chain, including thiol modification <400> 9 Ile Glu Glu Gln Ala Lys Thr Phe Leu Asp Lys Phe Asn His Glu Ala 1 5 10 15 Glu Asp Leu Phe Tyr Gln Ser Ser Xaa Gly Leu Gly Lys Gly Asp Phe 20 25 30 Arg Pagina 4

Claims (18)

ConclusiesConclusions 1. Verbinding, omvattende ten minste twee peptiden die fysiek gekoppeld zijn door een linker, waarbij elke peptide een aminozuursequentie TFLDKFNHEAEDLFYQ of een variant daarvan omvat.A compound comprising at least two peptides physically linked by a linker, each peptide comprising an amino acid sequence TFLDKFNHEAEDLFYQ or a variant thereof. 2. Verbinding volgens conclusie 1, omvattende twee peptiden, waarbij 1) beide peptiden aan de linker zijn bevestigd via hun N- terminus; 11) beide peptiden aan de linker zijn bevestigd via hun C-terminus; of iil) een peptide aan de linker is bevestigd via haar N-terminus en de andere peptide aan de linker is bevestigd via haar C-terminus.A compound according to claim 1, comprising two peptides, wherein 1) both peptides are attached to the linker through their N-terminus; 11) both peptides are attached to the linker through their C-terminus; or iii) one peptide is attached to the linker through its N-terminus and the other peptide is attached to the linker through its C-terminus. 3. Verbinding volgens conclusie 1, omvattende drie peptiden, waarbij 1) elke peptide aan de linker is bevestigd via haar N-terminus; 11) elke peptide aan de linker is bevestigd via haar C-terminus; u) twee peptiden aan de linker zijn bevestigd via hun N-terminus en een peptide aan de linker is bevestigd via haar C-terminus, of iv) twee peptiden aan de linker zijn bevestigd via hun C-terminus en een peptide aan de linker is bevestigd via haar N-terminus.The compound of claim 1, comprising three peptides, wherein 1) each peptide is attached to the linker through its N-terminus; 11) each peptide is attached to the linker through its C-terminus; u) two peptides are attached to the linker through their N-terminus and one peptide is attached to the linker through its C-terminus, or iv) two peptides are attached to the linker through their C-terminus and one peptide is attached to the linker attached through its N-terminus. 4. Verbinding volgens een der conclusies 1-3, waarbij de linker omvat - een trivalent atoom zoals stikstof, optioneel gesubstitueerd aryl, optioneel gesubstitueerd heteroaryl, optioneel gesubstitueerd cycloalkyl, of optioneel gesubstitueerd heterocycloalkyl, of - CR3 of SiR3, waarbij R3 waterstof of een label, zoals een PEG- label, een fluorescerend label, een isotoop, of een bio-orthogonaal handvat is.A compound according to any one of claims 1 to 3, wherein the linker comprises - a trivalent atom such as nitrogen, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl, or - CR 3 or SiR 3 , wherein R 3 is hydrogen or a label, such as a PEG label, a fluorescent label, an isotope, or a bio-orthogonal handle. 5. Verbinding volgens een der conclusies 1-4, waarbij de variant tot en met 5 van de volgende aminozuursubstituties heeft: substitutie van een of meer aminozuren gekozen uit de groep van L, I of A met een ander aminozuur gekozen uit L, I, V of A; substitutie van een of meer aminozuren gekozen uit de groep van K of H met een aminozuur gekozen uit R, Kof H; substitutie van E door Q substitutie van Y door F substitutie van een of meer aminozuren gekozen uit de groep van Q, N, A, S of T met een ander aminozuur gekozen uit genoemde groep; hebbende een of meer substituties van een aminozuur met een corresponderend D-aminozuur hebbende tot en met 5 substituties van een aminozuur met een corresponderend niet-natuurlijk aminozuur, en/of hebbende een retro-inverso-sequentie van ten minste 16 opeenvolgende aminozuren uit genoemde aminozuursequentie.A compound according to any one of claims 1-4, wherein the variant has up to 5 of the following amino acid substitutions: substitution of one or more amino acids selected from the group of L, I or A with another amino acid selected from L, I, V or A; substitution of one or more amino acids selected from the group of K or H with an amino acid selected from R, K or H; substitution of E by Q substitution of Y by F substitution of one or more amino acids selected from the group of Q, N, A, S or T with another amino acid selected from said group; having one or more substitutions of an amino acid with a corresponding D-amino acid, having up to and including 5 substitutions of an amino acid with a corresponding unnatural amino acid, and/or having a retro-inverso sequence of at least 16 contiguous amino acids from said amino acid sequence . 6. Verbinding volgens een der conclusies 1-5, waarbij de peptide voorts de sequentie LGKGDFR aan de C-terminuszijde van de peptide omvat.A compound according to any one of claims 1-5, wherein the peptide further comprises the sequence LGKGDFR on the C-terminus side of the peptide. 7. Verbinding volgens een der conclusies 1-6, waarbij de peptiden een of meer kruisverbindingen omvatten tussen zijketengroepen van aminozuren op posities 21 en 25, 22 en 26, 25 en 29, 28 en 32, 29 en 33, 32 en 36, 36 en 40, 39 en 43, en 40 en 44, of waarbij de peptiden een of meer kruisverbindingen omvatten tussen zijketengroepen van aminozuren op posities 21 en 28, 22 en 29, 25 en 32, 26 en 33, 29 en 36, 32 en 39, 33 en 40, 36en 43, 39 en 46.A compound according to any one of claims 1-6, wherein the peptides comprise one or more crosslinks between amino acid side chain groups at positions 21 and 25, 22 and 26, 25 and 29, 28 and 32, 29 and 33, 32 and 36, 36 and 40, 39 and 43, and 40 and 44, or wherein the peptides comprise one or more crosslinks between side chain groups of amino acids at positions 21 and 28, 22 and 29, 25 and 32, 26 and 33, 29 and 36, 32 and 39 , 33 and 40, 36 and 43, 39 and 46. 8. Verbinding volgens conclusie 7 waarbij de zijketenkruisverbindingen worden verkregen door lactamisering, thio-ethervorming, klikreacties en/of metathese.A compound according to claim 7 wherein the side chain crosslinks are obtained by lactamization, thioetherification, click reactions and/or metathesis. 9. Verbinding volgens een der conclusies 1-8, waarbij de verbinding een der volgende formules heeft: Mo, da} Vie, F ow, . bl, on 1, . zi, Ne do Heat, Sul == Wen,A compound according to any one of claims 1-8, wherein the compound has one of the following formulas: Mo, da} Vie, Fow, . bl, on 1, . zi, Ne do Heat, Sul == Wen, Ee = Gag, waarbij X —(CHg2):NHC(=0)CHa—, -CH:sNHC=0O)(CH>)2, ~-CH2NHC(=0)CHga—, — (CH2):NHC(=0)CHz)2—, ~C(=0)CHz:NHC(=0)CHgz—, ~C(=0)CHa—, — C(=0)(CHz)e—, -NHS@=0):(CHs)2-, ~-NHS(=0)2CHg—, —Ee = Gag, where X —(CHg2):NHC(=0)CHa—, -CH:sNHC=OO)(CH>)2, ~-CH2NHC(=0)CHga—, — (CH2):NHC(= 0)CH2)2—, ~C(=0)CH2—NHC(=0)CH2—, ~C(=0)CHa—, — C(=0)(CH2)e—, -NHS@=0) :(CHs)2-, ~-NHS(=0)2CHg—, — (CHg2)2NHS(=0)2(CHz)e—, —-CH2NHS(=0)2(CHz)2—, —(CH2)2: NHS(=0)2(CHz)2—, ~CH2NHS(=0)2CH2—, ~C(=0)CH2NHS(=0):CHz—, — C(=0)CH2NHS(=0)2(CHz)o—, —C(=0)(CH2)eNHS(=0)2CHo—, — C(=0)(CH2)2:NHS(=0)2(CHz)z—, -S(=0)2CHs-, ~CH:2S(=0)2CHg~, — S(=0)2(CHz)a—, —CH2S(=0)2(CHz)2—, (CH2)2S(=0)2(CHa)z—, —(CHg2)2NHS(=0)2(CH2)e—, —-CH2NHS(=0)2(CH2)2—, —(CH2)2: NHS(=0)2(CH2)2—, ~CH2NHS( =0)2CH2—, ~C(=0)CH2NHS(=0):CH2—, — C(=0)CH2NHS(=0)2(CH2)o—, —C(=0)(CH2)eNHS( =0)2CH2—, — C(=0)(CH2)2:NHS(=0)2(CH2)z—, -S(=0)2CHs-, ~CH:2S(=0)2CHg~, — S(=O)2(CH2 )a—, —CH2S(=O)2(CH2 )2—, (CH2)2S(=O)2(CHa)z—, — (CH2)2NHC(EO)NCH)2CHe—, —-CH2NHCEONCH)2(CHe)o—, — (CH2):NHC(=0)(CH)2(CHz)o—, —CH2NHC(=0)(CH)2CHo—, — C(=0)CH2NHC(=0)(CH)YCHe—, ~C(=0)CHNHC(=0)(CH)2(CHg)a—, — C(=0)(CHg)2NHC(=0)(CH)2CHz~, —C(=0)(CH2)2NHC=0)(CH)2(CHz)2—, C(=0)(CH)2:CHz—, —C(=0)(CH)2(CHg)o—, ~NHP(=O)(ORY)(CHz)2—, —(CH2)2NHC(EO)NCH)2CHe—, —-CH2NHCEONCH)2(CHe)o—, — (CH2):NHC(=0)(CH)2(CH2)o—, —CH2NHC(=0)( CH)2CHo—, — C(=0)CH2NHC(=0)(CH)YCHe—, ~C(=0)CHNHC(=0)(CH)2(CHg)a—, — C(=0)( CHg)2NHC(=0)(CH)2CH2~, —C(=0)(CH2)2NHC=0)(CH)2(CH2)2—, C(=0)(CH)2:CH2—, — C(=0)(CH)2(CH2 )o—, ~NHP(=O)(ORY)(CH2 )2—, — NHPEO)ORYH(CH)2—, -NHC(=0)(CH):CHz—, -NHC(=0)(CH)2(CHz)2—,NHPEO)ORYH(CH)2 --, -NHC(=O)(CH):CH2 --, -NHC(=O)(CH)2 (CH2 )2 --, deandean SK ~NHC(=0)N=S(CH3)—, -C(=O0)NH-, TON , optioneel gesubstitueerd x do ST Nak og, Ts LOR of afgeleiden daarvan omvat, waarbij R! alkyl, cycloalkyl of aryl is, en R? waterstof, alkyl, cycloalkyl of aryl is; WN, CR? of SiR3 is; R3 waterstof of een label is, zoals een PEG-label, een fluorescerend label of een isotoop; en QCHofNis of waarbij de verbinding een der volgende formules heeft: * De) DL ZORRA eT pact 2 (ia) of ee Tt ao, waarbij n een geheel getal van 1-100, bij voorkeur 2-10 is; L aminozuur, bij voorkeur glycine en/of serine is, en A -NHC@=O)CHs-, -CHsNHC(=0)-, -CH:NHC(=O)CHs-, — CHoNHC(=0)(CHg)o—, (CHs2NHC@=O)CH:-, <(CH>):NHC@=O)X(CHs)s-, —-CHCH:NHC(=0O)CHs-, -CHeNHC@=O)CHsCH-, -CH:NHC(=0)(CHz):CH-, -CH(CH>)2NHC{=0)CH2-, ~-CH(CHz):NHC(=0)(CH2)2—, | 3 x, of afgeleiden daarvan omvat; ae m een geheel getal van 1-100, bij voorkeur 2-10 is; © Y een afstandstuk is, bij voorkeur afgeleid van aminozuren, aminothiozuren, diprotische zuren, zoals dicarboxylzuren en dithiocarboxylzuren, diolen, zoals glycolen, en/of mercapto-alcoholen, en Z een peptide is zoals gedefinieerd in een der conclusies 1-6.SK ~NHC(=O)N=S(CH3)-, -C(=O0)NH-, TON , optionally substituted x do ST comprises Nak og, Ts LOR or derivatives thereof, wherein R! alkyl, cycloalkyl or aryl, and R? hydrogen, alkyl, cycloalkyl or aryl; WN, CR? or SiR 3 ; R 3 is hydrogen or a label, such as a PEG label, a fluorescent label or an isotope; and QCH or Nis or wherein the compound has one of the following formulae: * De) DL ZORRA eT pact 2 (ia) or ee Tt ao, wherein n is an integer of 1-100, preferably 2-10; L is amino acid, preferably glycine and/or serine, and A is -NHC®=O)CH 3 -, -CH 3 NHC(=0)-, -CH:NHC(=O)CH 3 -, - CHoNHC(=0)(CH 3 ) )o-, (CH3 2NHC@=O)CH:-, <(CH>):NHC@=O)X(CH3 )s-, --CHCH:NHC(=O)CH3 -, -CHeNHC@=O) CH3 CH-, -CH:NHC(=0)(CH2 ):CH-, -CH(CH>)2 NHC{=0)CH2-, ~-CH(CH2 ):NHC(=0)(CH2)2 --, | 3x, or derivatives thereof; ae m is an integer of 1-100, preferably 2-10; © Y is a spacer, preferably derived from amino acids, aminothioacids, diprotic acids, such as dicarboxylic acids and dithiocarboxylic acids, diols, such as glycols, and/or mercaptoalcohols, and Z is a peptide as defined in any one of claims 1-6. 10. Verbinding volgens een der conclusies 1-9, waarbij de verbinding een der volgende formules heeft: ee AE i “NH B STRETTON G RE Ss 6 - 8 9 NT Se GREER Ld x a Bs bd Y wr ee be ge ye A 5 Sa i re Q 3 5 Rey i < y § : - MH zw RE ~ A =p or No ~ Eye <3 B “3 5 a a (1d-C1, z Co 9 A f A . i. ws * CH eN 0 o \ es vj NR - $ NH Th of Serbo er Papo ® 3 Td-O2, : == > DR’ Voeg, i A fg i * Hen M.A compound according to any one of claims 1-9, wherein the compound has one of the following formulae: ee AE i ' NH B STRETTON G RE Ss 6-8 9 NT Se GREER Ld x a Bs bd Y wr ee bege ye A 5 Sa i re Q 3 5 Rey i < y § : - MH zw RE ~ A =p or No ~ Eye <3 B “3 5 a a (1d-C1, z Co 9 A f A . i. ws * CH eN 0 o \ es vj NR - $ NH Th or Serbo er Papo ® 3 Td-O2, : == > DR' Add, i A fg i * Hen M. La oO - „3 SF i ON i So bo Rr Say MHZ Ne ee meege oi 5 EE | 7 Co ef MZ gs A Si a ed oe G * {3d-C3), oy 0 3 pd 3 gs EOE p } TR he a o \ Bt Ra i 4 AN ee Dy HN 5 so © a Eda ha “ab Br Soe NE Oort * HESLa oO - „3 SF i ON i So bo Rr Say MHZ Ne ee meege oi 5 EE | 7 Co ef MZ gs A Si a ed oe G * {3d-C3), oy 0 3 pd 3 gs EOE p } TR he a o \ Bt Ra i 4 AN ee Dy HN 5 so © a Eda ha “ab Br Soe NE Oort * HES 0 o gf 5 8 ) ST pT ie WH 00m Ore N = Ned, ~ vd 4 u 3 a . / a Den, LH Ra ee JE SRT Ve gg de 3 ST NT HN 2 COR 3 (d-N2}, EEE i = ’ Wo 0 ml i ä Fo mn en i 4 { / en ee N2 cor® New mM LB ML 77 Te Bete { nN rine ea N-tl ; ge $ ~ | Seg ZR MH N ’8 va ~ om f (Td-N3), waarbij Z is zoals gedefinieerd in conclusie 7, en elke R+ onafhankelijk OH of NHbis.0 o gf 5 8 ) ST pT ie WH 00m Ore N = Ned, ~ vd 4 u 3 a . / a Den, LH Ra ee JE SRT Ve gg de 3 ST NT HN 2 COR 3 (d-N2}, EEE i = ' Wo 0 ml i ä Fo mn en i 4 { / and ee N2 cor® New mM LB ML 77 Te Bete { nN rine ea N-tl ; ge $ ~ | Seg ZR MH N '8 va ~ om f (Td-N3), where Z is as defined in claim 7, and each R+ is independently OH or NHbis. 11. Farmaceutische samenstelling omvattende een verbinding volgens een der conclusies 1-10.A pharmaceutical composition comprising a compound according to any one of claims 1-10. 12. Verbinding volgens een der conclusies 1-10 voor toepassing als een geneesmiddel.A compound according to any one of claims 1-10 for use as a medicament. 13. Verbinding volgens een der conclusies 1-10 of een farmaceutische samenstelling volgens conclusie 11 voor toepassing bij de preventie of behandeling van een infectie veroorzaakt door een virus dat een cel kan binnendringen via de angiotensine-omzettende-enzym-2-(ACE2)-receptor, bij voorkeur een coronavirus.A compound according to any one of claims 1-10 or a pharmaceutical composition according to claim 11 for use in the prevention or treatment of an infection caused by a virus capable of entering a cell via the angiotensin converting enzyme-2-(ACE2)- receptor, preferably a coronavirus. 14. Werkwijze voor het remmen van infectie van een cel die permissief is voor coronavirus, omvattende: - verschaffen aan de cel een verbinding volgens een der conclusies 1-10 of een farmaceutische samenstelling volgens conclusie 11.A method of inhibiting infection of a cell permissive to coronavirus, comprising: providing the cell with a compound according to any one of claims 1-10 or a pharmaceutical composition according to claim 11. 15. Werkwijze voor het behandelen van een infectie veroorzaakt door een virus dat een cel kan binnendringen via de ACE2-receptor, bij voorkeur een coronavirus in een individu, omvattende: - toedienen van een verbinding volgens een der conclusies 1-10 of een farmaceutische samenstelling volgens conclusie 11 aan het individu.A method of treating an infection caused by a virus capable of entering a cell via the ACE2 receptor, preferably a coronavirus in an individual, comprising: - administering a compound according to any one of claims 1-10 or a pharmaceutical composition according to claim 11 to the individual. 16. Verbinding voor toepassing volgens conclusie 13 of de werkwijze volgens conclusie 14 of 15, waarbij het coronavirus gebruik maakt van de ACE2-receptor om toegang tot een cel te verkrijgen.A compound for use according to claim 13 or the method according to claim 14 or 15, wherein the coronavirus uses the ACE2 receptor to gain entry into a cell. 17. Verbinding voor toepassing volgens conclusie 13 of 16, of de werkwijze volgens conclusie 14-16, waarbij het coronavirus een bètacoronavirus is.A compound for use according to claim 13 or 16, or the method according to claim 14-16, wherein the coronavirus is a beta-coronavirus. 18. Verbinding voor toepassing volgens een der conclusies 13, 16, of 17, of de werkwijze volgens een der conclusies 14-17, waarbij het coronavirus een ernstig acuut respiratoir syndroom (severe acute respiratory syndrome) gerelateerd coronavirus is of een Midden-Oosten respiratoir syndroom (Middle East respiratory syndrome) gerelateerd coronavirus, bij voorkeur SARS-CoV, SARS-CoV-2 of MERS-CoV.A compound for use according to any one of claims 13, 16, or 17, or the method according to any one of claims 14-17, wherein the coronavirus is a severe acute respiratory syndrome related coronavirus or a Middle Eastern respiratory syndrome (Middle East respiratory syndrome) related coronavirus, preferably SARS-CoV, SARS-CoV-2 or MERS-CoV.