Neutralizing polypeptides and their applications

Abstract

Neutralizing polypeptides and their applications The present invention aims to provide novel polypeptides of formula (I) and pharmaceutical compositions comprising such polypeptides. These novel polypeptides of formula (I) or pharmaceutical compositions can be used as a medicament for treating and / or preventing diseases or conditions caused by infection with a virus of the SARS-CoV species, in particular SARS-CoV-2. Figure for abstract: None

Description

Title of the invention: Neutralizing polypeptides and their applications Technical field

[0001] The present disclosure relates to novel artificial polypeptides, in particular novel HEAT-like alpha-helical repeat proteins (aRep). The present disclosure also relates to the use of these novel polypeptides as a medicament, in particular for the treatment and prevention of diseases and / or conditions caused by infection with a virus of the species SARS-CoV, in particular SARS-CoV-2. Prior art

[0002] Viruses are one of the leading causes of disease worldwide. Viruses are generally defined as small, non-living infectious agents that replicate only within living cells, as they do not possess a completely autonomous replication mechanism. Although they come in various shapes and sizes, they generally consist of a viral particle (called a "virion"), made up of a protein envelope that includes at least one nucleic acid molecule and possibly, depending on the type of virus, one or more proteins or nucleoproteins.

[0003] Although their replication cycle varies greatly from one species to another, it is generally accepted that the life cycle of viruses includes six fundamental stages: attachment, penetration, uncoating, replication, assembly and release.

[0004] Depending on the nature of the targeted virus, therapeutic solutions have been designed to interfere with one or more of these mechanisms.

[0005] Viruses are classified according to their genome type. The current classification of viruses, as of 2018, includes seven different groups:

[0006] - Group I: double-stranded DNA (dsDNA) viruses;

[0007] - Group II: single-stranded DNA viruses (sDNA);

[0008] - Group III: double-stranded RNA viruses (dsRNA);

[0009] - Group IV: (+) strand or sense ((+)ssRNA) RNA virus;

[0010] - Group V: (-) stranded or antisense ((-)ssRNA) RNA virus;

[0011] - Group VI: single-stranded RNA viruses having DNA intermediates (sRNA-TR); And

[0012] - Group VII: double-stranded DNA viruses having RNA intermediates (dsDNA- TR).

[0013] There are few cures for diseases caused by infections with RNA viruses, particularly single-stranded RNA viruses, and more specifically infections by RNA viruses belonging to group IV of the Baltimore classification.

[0014] In December 2019, a new coronavirus (SARS-CoV-2), also known as coronavirus 2019 (COVID-19), was recently discovered. This new coronavirus belongs to the Coronaviridae family, the SARS-CoV species, and is part of group IV of the Baltimore classification.

[0015] The World Health Organization (WHO) has officially declared the COVID-19 pandemic a public health emergency of international concern. This novel coronavirus spreads primarily through the respiratory tract and causes acute respiratory illness. Older adults and those with underlying medical conditions are susceptible to infection and prone to severe outcomes, which may be associated with acute respiratory distress syndrome (ARDS).

[0016] This coronavirus is a single-stranded, positive-polarity RNA virus of approximately 30 kilobases that replicates in the cytoplasm of host cells. This virus is enveloped and includes, on its surface, peplomeric structures called spicules consisting of the Spike (S) protein.

[0017] The Spike or S protein is a membrane glycoprotein (200-220 kDa) that appears as spikes emerging from the surface of the viral envelope. This surface S protein binds to the ACE2 cellular receptor, which is expressed in many tissues. It contains two subunits (SI and S2), SI including the receptor binding domain (RBD) containing the receptor binding motif (RBM) and S2 containing the fusion peptide that induces fusion of the viral envelope with the cell membrane. The S protein is the primary target of the neutralizing antibody response.

[0018] Several therapeutic strategies are currently being explored, including limiting the spread of infection by viruses of the SARS-CoV species by blocking virus replication. This can be done by preventing the entry of the virus into target cells in the lungs and other tissues by targeting the S protein and mainly its RBD domain (receptor binding domain of the S1 subunit of the Spike protein).

[0019] This neutralization of the S protein can be done, in particular, using natural or artificial proteins, such as:

[0020] - human monoclonal antibodies, the cost of which is substantial and reserved for very special cases,

[0021] - VHH (Recombinant Llama Antibodies) derivatives that should be used by chimerizing VHHs to make VHH-Fcs that can be recognized by the patient's immune system,

[0022] - DARPins (Designed Ankyrin Repeat Proteins), and

[0023] - the miniproteins developed by the group of David Baker (University of Washington, Seattle).

[0024] The implementation of these therapeutic solutions is very uncertain at present and requires the exploration of other options.

[0025] Thus, there is a need for new compounds for treating or preventing infection by a virus of the SARS-CoV species, in particular SARS-CoV-2.

[0026] There is a need for novel proteins having strong neutralizing activity against a virus of the SARS-CoV species, in particular SARS-CoV-2.

[0027] There is a need for novel proteins having strong protective activity against infection with a virus of the SARS-CoV species in an individual, in particular SARS-CoV-2.

[0028] There is a need for new proteins having a strong protective activity against infection with a virus of the SARS-CoV species in an individual, in particular SARS-CoV-2, with a low production cost.

[0029] There is a need for new proteins having strong protective activity against infection with a virus of the SARS-CoV species in an individual, in particular SARS-CoV-2, with improved production yield.

[0030] There is a need for novel proteins having strong neutralizing activity against a virus of the SARS-CoV species, in particular SARS-CoV-2, causing little, if any, immune response in an individual.

[0031] The present invention aims to meet all or part of these needs. Statement of the present description

[0032] The inventors have developed novel peptides for treating and / or preventing infection by a virus of the SARS-CoV species, in particular SARS-CoV-2. Unexpectedly, the inventors observed that a plurality of artificial polypeptides, called aReps, as defined in the present description had neutralizing activity for the SARS-CoV-2 virus. Surprisingly, and contrary to the teaching of the prior art concerning human monoclonal antibodies (Bames et al. Nature 588, 682-687, 2020; Baum et al. Science 370, 1110-1115, 2020; Chen et al. N. Engl. J. Med, 2020; Fagre et al. Front Immunol 11:614256, 2020; Hansen et al. Science 369, 1010-1014, 2020; Li et al. Proc. Natl. Acad. Sci. USA 117, 29832-29838, 2020; Li et al. Cell 183, 429-441.e416, 2020; Raybould et al. Bioinformatics, btaa739, 2020), nanobodies / VHH (Custodio et al. Nat Commun, 2020; Czajka et al. Prends in Microbiology 29, 195-203; Güttler et al. EMBO J.el07985, 2021; Hanke et al. Nat. Struct. Mol. Biol. 27, 846-854, 2020; Ma et al. J Viral. 95:e02438-20, 2021; Schoof et al. Science 370, 1473-1479, 2020; Wrapp et al. Cell 181, 1004-1015.el015, 2020; Xiang et al. Science, 2020), small inhibitory proteins (Cao et al. Science 370:426-431, 2020) or DARPINs. (Walser et al. 2020), these polypeptides have a high affinity to the RBD domain of the S1 subunit of the S protein of viruses of the SARS-CoV species, in particular the aReps C2, H12 and F9. In addition, these artificial polypeptides have the advantage of having a low production cost and facilitated production in E. coli bacteria. In addition, due to their small size (for example, 170 amino acids for the C2 polypeptide) the artificial polypeptides of the present description are poorly immunogenic, or even non-immunogenic. These new compounds are HEAT-type alpha-helical repeat proteins (aReps) which have the capacity to recognize and bind specifically to the RBD domain of the S protein of viruses of the SARS-CoV species, in particular SARS-CoV-2, in order to neutralize and block the attachment of the virus to its target cell.

[0033] The peptides according to the present description would also exhibit increased virus neutralization activity in the form of homologous or heterologous multimerization. The peptides described herein also have the advantage of being highly soluble in water.

[0034] Thus, the present invention aims to provide new polypeptides and pharmaceutical compositions comprising such polypeptides. These new polypeptides or pharmaceutical compositions can be used as a medicament for treating and / or preventing diseases or conditions caused by an infection by a virus of the SARS-CoV species, in particular SARS-CoV-2. Summary of the present description

[0035] According to one of its objects, the present description relates to a polypeptide of formula (I)

[0036] NH2-[Nt]-[SBP]z-[Ct]-COOH (I),

[0037] in which:

[0038] - z is an integer from 1 to 10;

[0039] - Nt comprises a peptide selected from SEQ ID NO. 20, SEQ ID NO. 21, SEQ ID NO. 22, SEQ ID NO. 23, SEQ ID NO. 24, SEQ ID NO. 25, SEQ ID NO. 26, SEQ ID NO. 27, SEQ ID NO. 28, SEQ ID NO. 29 SEQ ID NO. 42, SEQ ID NO. 43, SEQ ID NO. 44, SEQ ID NO. 45, SEQ ID NO. 46, SEQ ID NO. 47, SEQ ID NO. 48, SEQ ID NO. 49, SEQ ID NO. 50, SEQ ID NO. 51, SEQ ID NO. 52 et SEQ ID NO. 53 ;

[0040] - Ct comprises a peptide having a length of from 1 to 100 amino acids; et

[0041] - SBP comprises a peptide, the varying amino acids of which are identical or different from one SBP to another, of formula (II)

[0042] NH2 - [SEQ ID NO. 16] - X1-X2-VR-X3-X4-AA-X5-ALG-X6-I - COOH (II)

[0043] wherein:

[0044] - XI is an amino acid selected from A (Alanine), E (Glutamic Acid), T (Threonine), S (Serine), P (Proline), V (Valine), G (Glycine), L (Leucine), K (Lysine), R (Arginine), W (Tryptophan), Y (Tyrosine);

[0045] - X2 is an amino acid chosen from N (Asparagine), A (Alanine), D (Acid aspartic acid), T (Threonine), R (Arginine), S (Serine), Q (Glutamine), Y (Tyrosine), G (Glycine), E (Glutamic Acid), L (Leucine), F (Phenylalanine), W (Tryptophan), N (Asparagine), ;

[0046] - X3 is an amino acid chosen from I (Isoleucine), Q (Glutamine), R (Arginine), Y (Tyrosine), K (Lysine), T (Threonine), V (Valine), L (Leucine), A (Alanine), F (Phenylalanine), E (Glutamic Acid), S (Serine), M (Methionine), W (Tryptophan);

[0047] - X4 is an amino acid chosen from S (Serine), E (Glutamic Acid), T (Threonine), A (Alanine), R (Arginine), G (Glycine), L (Leucine), V (Valine), N (Asparagine);

[0048] - X5 is an amino acid chosen from A (Alanine), S (Serine), R (Arginine), T (Threonine), N (Asparagine), F (Phenylalanine), V (Valine), G (Glycine), L (Leucine), D (Aspartic Acid), Y (Tyrosine), K (Lysine), R (Arginine), E (Glutamic Acid), W (Tryptophan), N (Asparagine), Q (Glutamine), I (Isoleucine); and

[0049] - X6 is an amino acid selected from K (Lysine), Q (Glutamine), E (Acid Glutamic).

[0050] According to certain embodiments, the SBP of formula (II) as described herein may comprise:

[0051] - XI, this being an amino acid chosen from A (Alanine), E (Glutamic Acid), T (Threonine), S (Serine), P (Proline), V (Valine), G (Glycine), L (Leucine), K (Lysine), R (Arginine), W (Tryptophan);

[0052] - X2, this being an amino acid chosen from N (Asparagine), A (Alanine), D (Aspartic Acid), T (Threonine), R (Arginine), S (Serine), Q (Glutamine), Y (Tyrosine), G (Glycine), E (Glutamic Acid), L (Leucine), F (Phenylalanine), W (Tryptophan);

[0053] - X3, this being an amino acid chosen from I (Isoleucine), Q (Glutamine), R (Arginine), Y (Tyrosine), K (Lysine), T (Threonine), V (Valine), L (Leucine), A (Alanine), F (Phenylalanine);

[0054] - X4, this being an amino acid chosen from S (Serine), E (Glutamic Acid), T (Threonine), A (Alanine), R (Arginine), G (Glycine), L (Leucine), V (Valine), N (Asparagine);

[0055] - X5, this being an amino acid chosen from A (Alanine), S (Serine), R (Arginine), T (Threonine), N (Asparagine), F (Phenylalanine), V (Valine), G (Glycine), L (Leucine), D (Aspartic Acid), Y (Tyrosine), K (Lysine), R (Arginine), E (Glutamic Acid), W (Tryptophan), N (Asparagine), Q (Glutamine); and

[0056] - X6, this being an amino acid chosen from K (Lysine), Q (Glutamine), E (Acid Glutamic).

[0057] According to certain embodiments, the integer z, of the polypeptide of formula (I), can be an integer from 3 to 8.

[0058] According to certain embodiments, Nt, of the polypeptide of formula (I), can be chosen from the peptides of sequence SEQ ID NO. 20, SEQ ID NO. 21, SEQ ID NO. 22, SEQ ID NO. 23, SEQ ID NO. 24, SEQ ID NO. 25, SEQ ID NO. 26, SEQ ID NO. 27, SEQ ID NO. 28 and SEQ ID NO. 29.

[0059] According to certain embodiments, Ct, of the polypeptide of formula (I), may consist of a peptide having a length of 1 to 50 amino acids,

[0060] According to certain preferred embodiments, Ct of the polypeptide of formula (I) may consist of a peptide having a length of 1 to 36 amino acids, more preferably a peptide of 36 amino acids.

[0061] According to certain embodiments, Ct, of the polypeptide of formula (I), may consist of a peptide of sequence SEQ ID NO. 18.

[0062] According to certain particular embodiments, the polypeptide of formula (I) may be chosen from the peptides of sequence SEQ ID NO. 1, SEQ ID NO. 2, SEQ ID NO. 3, SEQ ID NO. 4, SEQ ID NO. 5, SEQ ID NO. 6, SEQ ID NO. 7, SEQ ID NO. 8, SEQ ID NO. 9, SEQ ID NO. 10, SEQ ID NO. 30, SEQ ID NO. 31, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 34, SEQ ID NO. 35, SEQ ID NO. 36, SEQ ID NO. 37, SEQ ID NO. 38, SEQ ID NO. 39, SEQ ID NO. 40 and SEQ ID NO.41.

[0063] According to another of its objects, the present description also relates to a composite polypeptide comprising a plurality of polypeptides of formula (I) according to the present description or a polypeptide of formula (I) covalently linked by its amino acid residue at the N-terminus to a peptide of sequence SEQ ID NO.54.

[0064] According to certain embodiments, a composite polypeptide according to the disclosure may consist of a dimer or trimer of a polypeptide of formula (I) as described herein.

[0065] According to certain embodiments of a composite polypeptide in the form of a dimer or trimer of the polypeptide of formula (I) as described herein, the polypeptides of formula (I) may be linked by a linker peptide, preferably a linker peptide of sequence SEQ ID NO. 19

[0066] According to certain preferred embodiments of a composite polypeptide, the polypeptides of formula (I) may be chosen from the peptides of sequence SEQ ID NO. 1, SEQ ID NO. 7 and SEQ ID NO. 10.

[0067] According to certain other preferred embodiments of a composite polypeptide according to the present disclosure, the composite polypeptide may be selected from peptides of sequence SEQ ID NO. 11, SEQ ID NO. 12, SEQ ID NO. 13, SEQ ID NO. 14 and SEQ ID NO. 15.

[0068] According to another of its objects, the present description also relates to a pharmaceutical composition comprising a polypeptide of formula (I) or a composite polypeptide as described in the present description, in combination with at least one pharmaceutically or physiologically acceptable vehicle.

[0069] According to another of its objects, the present description also relates to a polypeptide of formula (I), a composite polypeptide or a pharmaceutical composition as described in the present description, for use as a medicament.

[0070] According to another of its objects, the present description also relates to a polypeptide of formula (I), a composite polypeptide or a pharmaceutical composition as described in the present description, for use in the treatment and / or prevention in an individual of a condition caused by an infection by a virus of the species SARS-CoV, in particular SARS-CoV-2.

[0071] According to another of its objects, the present description also relates to a method of treating and / or preventing a condition caused by an infection by a virus of the SARS-CoV species, in particular SARS-CoV-2, in an individual in need thereof, comprising a step of administering to the individual a polypeptide of formula (I), a composite polypeptide or a pharmaceutical composition as described in the present description.

[0072] According to another of its objects, the present description also relates to the use of a polypeptide of formula (I), of a composite polypeptide or of a pharmaceutical composition as described in the present description for obtaining a medicament intended to treat and / or prevent a condition caused by an infection by a virus of the SARS-CoV species, in particular SARS-CoV-2, in an individual in need thereof. Brief description of the drawings

[0073] [Fig-1] shows that aReps C2, C12, F9, Gl, H10 and H12 have low velocities of dissociation unlike aReps C7, D7 and F7. [Fig.l] represents the fixation of aReps H7 (negative control), C7, H10, C12, F9, F7, D7, Gl and C2 concentrated at 1 pM on the RBD domain of the SARS-CoV-2 virus by bi-layer interferometry. Abscissa: Time in seconds. Ordinate: Thickness of the bi-layer on the sensor (expressed in nm)

[0074] [Fig.2A-2B-2C-2D] and [Fig.2E] show that the aReps C2 and F9 have an affinity high binding for the RBD domain and the SI subunit (the N-ter domain of the S protein) of SARS-CoV-2. [Fig.2A-2B-2C-2D] and [Fig.2E] represent the binding of aReps C2, F9 and the F9-C2 dimer to the RBD domain of the SI subunit analyzed by bi-layer interferometry. 2A represents the binding of aRep C2 on the RBD domain. 2B represents the binding of aRep C2 to the SI subunit. 2C represents the binding of aRep F9 to the RBD domain. 2D represents the binding of aRep F9 to the SL subunit [Fig.2E] represents the binding of the composite aRep F9-C2 to the SL subunit Abscissa: Time in seconds. Ordinate: Thickness of the bilayer on the sensor (expressed in nm).

[0075] [Fig.3A-3B] show that aReps C2, C7, F9 and H12 neutralize particles pseudotyped S protein and SARS-CoV-2 virus and protect from infection depending on their concentrations. Three biological replicates per concentration were performed. Error bars represent the standard deviation from the mean. 3A represents the infection rate of HEK-293T cells expressing ACE2 by pseudotyped murine leukemia virus (MLV) particles carrying the SARS-CoV-2 S protein in the presence of aReps H12, C2, Gl, F9, C7 and H7 (negative control) after 24 h of contact. Abscissa: aReps tested at concentrations of (a) 3 pM (black), (b) 600 nM (medium gray), or (c) 60 nM (dark gray) in cell culture medium and (d) VSVG (infection inhibition specificity control): cells infected with MLV-like particles carrying the vesicular stomatitis virus G protein (VSVG) with aReps tested at 3 pM (from left to right) H12, C2, Gl, F9, C7, H7, or phosphate-buffered saline (PBS). Ordinate: Percentage infection rate of HEK 293T cells by particles pseudotyped with the S (SARS-CoV-2) or G protein (VSVG). Figure 3B represents the infection rate of Vero-E6 cells by the SARS-CoV-2 virus in the presence or absence of aReps in DMEM medium (n=3). Abscissa: Concentration of aReps C2, C7, F9, G1, H12 and H7 in the cell culture medium in log10 (nM). Cells were infected without aRep (virus alone) or uninfected (medium alone). Ordinate: Viability of Vero-E6 cells infected with the SARS-CoV-2 virus in the presence of aReps (in arbitrary luminescence units).

[0076] [Fig.4A-4B] show that the composite aRep F9-C2 neutralizes the infection of cells HEK 293T by MLV-pseudotyped particles carrying the S protein or by the SARS-CoV-2 virus. Three biological replicates per concentration. Error bars represent the standard deviation from the mean. Figure 4A represents the inhibition of infection of HEK-293T cells expressing ACE2 by MLV-pseudo-typed particles with SARS-CoV-2 S protein in the presence of the composite F9-C2 aRep and the F9, C2 and H7 aReps (negative control). Abscissa: HEK-293T cells in the presence of mixtures of (a) 100 nM (black), (b) 10 nM (dark grey), (c) 1 nM (medium grey) aRep with SARS-CoV-2 S protein-pseudo-typed particles or (d) by cells infected with pseudo-typed MLV particles carrying the vesicular stomatitis virus G protein (VSVG - light gray) with aReps at a concentration of 3 μM (control of specificity of infection inhibition). Ordinate: Percentage infection rate of HEK 293T cells by particles pseudotyped with the S (SARS-CoV-2) or G (VSVG) protein. 4B represents the inhibition of infection of Vero-E6 cells by SARS-CoV-2 viruses. Abscissa: Concentration in pM of aReps C2, F9-C2, F9 + C2 and H7 in the culture medium of infected cells. Cells were infected without aRep (viruses alone) or uninfected (cells alone). Ordinate: Viability of Vero-E6 cells infected with the SARS-CoV-2 virus in the presence of aReps (in arbitrary luminescence units).

[0077] [Fig.5] shows that the composite aReps C2-foldon and F9-foldon have activity similar or even superior neutralizing activity on SARS-CoV-2 infection compared to F9 and C2 aReps alone and F9-C2. Three biological replicates per concentration were performed. Error bars represent the standard deviation from the mean. Abscissa: Concentration in pM of C2-foldon (■), F9-foldon (star), F9-C2 (A), F9 (▼), C2 (•) and H7 (O) aReps in the culture medium of SARS-CoV-2 infected cells. Ordinate: Viability of Vero-E6 cells infected with SARS-CoV-2 virus in the presence of aReps (in arbitrary luminescence units).

[0078] [Fig.6a-6b] and [Fig.6c-6d-6e] show that the aReps F9, C2 and F9-C2 have a Neutralizing activity on SARS-CoV-2 S protein mutants. All four variants analyzed (alpha, beta, gamma, and kappa) are more sensitive to neutralization of the composite F9-C2 aRep than the F9 and C2 aReps alone, highlighting the cooperative effect associated with the fusion of F9 and C2. Figure 6a represents the inhibition of infection of ACE2-expressing HEK-293T cells by retroviruses pseudotyped with the SARS-CoV-2 S protein (from the Wuhan-Hu-1 isolate). Also shown is the inhibition of infection of HEK-293T cells expressing ACE2 by retroviruses pseudotyped with S protein mutants: N501Y (6b), K417N, E484K, N501Y (6c), K417T, E484K, N501Y (6d) and L452R, E484Q (6e). Three biological replicates per concentration were performed. Error bars represent the standard deviation from the mean.Abscissa: HEK-293T cells in the presence of mixtures of (top to bottom) 500 nM, 250 nM, 100 nM, 50 nM or 10 nM aRep with particles pseudotyped with the SARS-CoV-2 S protein, and VSVG (control of specificity of infection inhibition): Cells infected with MLV pseudoparticles carrying the vesicular stomatitis virus G protein (VSVG) with aReps at a concentration of 3 rnM. Ordinate: Percentage infection rate of HEK 293T cells by particles pseudotyped with the S (SARS-CoV-2) or G (VSVG) protein.

[0079] [Fig.7A-7B] show that the composite aRep F9-C2 allows a reduction of SARS-CoV-2 infection in vivo compared to control H7 aRep in a hamster model. 7A represents the relative expression of the SARS-CoV-2 E protein reflecting the presence of the virus in the presence of aRep H7 (white dot) or F9-C2 (black dot) in the olfactory mucosa and lungs at day 1 (D1) or day 3 (D3) post-infection. Abscissa: Sampling at D1 and D3 post-infection of the olfactory mucosa and lungs of hamsters that received by nasal inoculation aRep H7 or F9-C2 1 h before infection with the SARS-CoV-2 virus. Ordinate: Relative expression in log of the E protein of the SARS-CoV-2 virus. Figure 7B represents the viral titer of nasal swabs reflecting the production of the SARS-CoV-2 virus by the nasal cavity of infected hamsters over 3 days post-infection. Abscissa: Days post-infection with SARS-CoV-2 (dpi). Ordinate: Viral titer of nasal swabs (log TCID5o) of hamsters that received by nasal inoculation of aRep H7 or F9-C2 1 h before infection with the SARS-CoV-2 virus. Detailed Description Definitions

[0080] The terms used in this description are used with their usual meaning in the technical field considered, and with regard to the context of the description in which the terms are used. Certain terms are further discussed below, or elsewhere in the description, to provide additional guidance with regard to this description and its implementation. The following definitions are provided for the description and the claims.

[0081] By "alphaRep" or "aRep" protein is meant an artificial polypeptide or protein comprising n repetitions of a 31 amino acid motif derived from HEAT proteins in which only 6 of them are variable and form the concave surface of the polypeptide. These polypeptides are capable of binding a ligand of interest or of neutralizing viruses, in particular viruses of the SARS-CoV species, in particular SARS-CoV-2. In the context of the present description, an aRep protein corresponds to a polypeptide of formula (I) as described and illustrated in the present description.

[0082] By "target cell" is meant here a cell which expresses a target antigen capable of being recognized by a polypeptide according to the present description, in particular a cell which expresses the ACE2 cellular receptor capable of being recognized by the S protein, in particular the RBD domain, of viruses of the SARS-CoV species, in particular SARS-CoV-2, and of conferring susceptibility to the virus. For example, a target cell can be a lung cell, an arterial cell, a heart cell, a kidney cell or a digestive system cell.

[0083] The description of the various embodiments of the present disclosure includes embodiments including "comprising", "having" and "consisting of". The words "have" and "comprise", or variations such as "has", "have", "comprises" or "comprising" are to be understood as implying the inclusion of the indicated element(s) (such as an element of a composition or a method step) but not the exclusion of other elements. The term "consisting of" implies the inclusion of the indicated element(s) to the exclusion of any additional elements.

[0084] As used herein, a "condition caused by infection" with a virus of the species SARS-CoV, may be selected from a list comprising or consisting of: severe respiratory distress syndrome, a cardiovascular condition, a vascular condition, a gastrointestinal condition or a neurological condition.

[0085] Advantageously, patients presenting, or at risk of presenting, a condition linked to an infection with a virus of the SARS-CoV species, in particular SARS-CoV-2, can also be taken into account.

[0086] For example, conditions caused by infection with a virus of the SARS-CoV species, including SARS-CoV-2, that are of particular concern include: pulmonary fibrosis, vasculitis, Kawasaki disease, and tissue damage or destruction, particularly damage and destruction of lung tissue and endothelia.

[0087] The term "individual" as used in the present description refers in particular to a mammal. Mammals considered include, but are not limited to, domestic animals (e.g., cattle, sheep, cats, dogs, and horses), primates (e.g., humans and non-humans), rabbits, and rodents (e.g., mice and rats). In a particular embodiment, an individual is a human being.

[0088] By "pharmaceutically acceptable" or "physiologically acceptable" is meant that the vehicle (carrier, diluent, or excipient) must be compatible with the other ingredients of the formulation, and not harmful to the individual to whom the composition comprising it is administered. A pharmaceutically or physiologically acceptable vehicle is a vehicle recognized as satisfying, in particular, the criteria of safety, compatibility, and inertness required for implementation in the pharmaceutical field. In particular, a physiologically acceptable vehicle is a substance or composition whose administration to an individual is not accompanied by significant deleterious effects. In particular, such a vehicle is compatible with oral or rectal administration, and preferably is suitable for administration by the oral route. As examples of a pharmaceutically acceptable vehicle or physiologically acceptable, it is possible to cite sterile water, saccharides such as sucrose or saccharose, starches, sugar alcohols such as sorbitol, polymers such as PVP or PEG, lubricating agents, such as magnesium stearate, preservatives, coloring or flavoring agents.

[0089] The list of sources, ingredients and components indicated below are understood to be described such that all combinations and mixtures thereof are also contemplated within the scope of the present invention.

[0090] The terms “prevent”, “prevention” (and variants of these expressions) with respect to a physiological disorder or disease caused by infection with a virus of the species SARS-CoV, in particular SARS-CoV-2, relate to the prophylactic treatment of the disease or disorder, for example in an individual infected with a virus of the species SARS-CoV, in particular SARS-CoV-2, and at risk of developing a disease or disorder related to this infection. Preventing includes, but is not limited to, preventing or slowing the development of the disease, and / or maintaining one or more disease symptoms at a desired or lesser level. The term “prevent” does not require 100% elimination of the possibility or probability of occurrence of the disease or disorder.Rather, this term refers to the reduction to a lesser degree of the risk or probability of occurrence of a given phenomenon linked to an infection by a virus of the species SARS-CoV, in particular SARS-CoV-2. As indicated, prevention can be complete, i.e. the absence of symptoms or detectable disease, or partial, such that there are fewer symptoms or the symptoms are of lesser intensity although the virus remains detectable in the infected individual.

[0091] In the context of the present invention, the term "SARS-CoV" refers to a virus belonging to the viral species Severe acute respiratory syndrome-related coronavirus and is a member of the genus Betacoronavirus and the subgenus Sarbecovirus (subgroup B) in the family Coronaviridae and the subfamily Orthocoronavirinae. The term SARS-CoV includes, but is not limited to, the strains SARS-CoV (or SARS-CoV-1), SARSr-CoV WIV1, SARSr-CoV HKU3, SARSr-CoV RP3, SARS-CoV-2; including the strains responsible for COVID-19, their mutants and variants. Viruses of the species SARS-CoV are preferably SARS-CoV-2 viruses. As is known, viruses of the SARS-CoV species include an RBD domain on the S protein, conserved between each strain of the species (Jaimes et al. Journal of Molecular Biology (2020) 432, 3309-3325).According to certain embodiments, a virus of the species SARS-CoV is characterized by at least one RBD domain having at least 72% amino acid identity with the peptide of sequence SEQ ID NO. 56. According to certain preferred embodiments, a virus of the species SARS-CoV is characterized by at least one protein of sequence SEQ ID NO. 56 (RBD domain). In some embodiments, a virus of the species SARS-CoV may be a SARS-CoV-2.

[0092] By "SARS-CoV-2" is meant a virus belonging to the species SARS-CoV, to the family Coronaviridae and part of group IV of the Baltimore classification. SARS-CoV-2 is also known as coronavirus 2019 (COVID-19) and stands for “severe acute respiratory syndrome coronavirus 2” in English. SARS-CoV-2 is a virus that spreads primarily through the respiratory tract and causes acute respiratory illness. The SARS-CoV-2 virus collectively refers to all strains responsible for COVID-19 and its mutants, such as the wild-type Wuhan-Hu-1 (NCBI Reference Sequence: NC_045512.2), the alpha variant carrying the N501Y substitution according to EU numbering, compared to the SARS-CoV-2 S protein (B.1.1.7), the beta variant carrying the K417H, E484K, N501Y substitutions in the RBD domain according to EU numbering, compared to the SARS-CoV-2 S protein (B.1.1.7).351), the gamma variant carrying the substitutions K417T, E484K and N501Y in the RBD domain according to EU numbering, compared to the SARS-CoV-2 S protein (Pl), the delta variant (Bl617.2) carrying the substitutions L452R and T478K in the RBD domain according to EU numbering, and the kappa variant (Bl617.1) carrying the substitutions L452R and E484Q in the RBD domain according to EU numbering, compared to the SARS-CoV-2 S protein.

[0093] SARS-CoV-2 is notably described in the document Dhama K, Khan S, Tiwari R, et al. Coronavirus Disease 2019-COVID-19. Clin Microbiol Rev. 2020;33(4):e00028-20. Published 2020 Jun 24. doi:10.1128 / CMR.00028-20.

[0094] In the context of the present description, the term "S protein" or "Spike protein" means a membrane glycoprotein (200-220 kDa) present on the surface of the viral envelope of viruses of the SARS-CoV species which binds to the cellular receptor ACE2. The S protein contains 2 subunits (SI and S2), SI including the receptor binding domain (RBD) containing the receptor binding motif (RBM) and S2 containing the fusion peptide allowing the induction of fusion of the viral envelope with the cell membrane. The S protein of SARS-CoV-2 is registered under the reference Gene ID: 43740568.

[0095] In the context of the present description, "E protein" or "envelope protein" means a 100-residue polypeptide that contains at least one α-helical transmembrane domain and a group of 2-3 juxtamembrane cysteines. The E protein is involved in several processes of the virus life cycle, such as assembly, budding, envelope formation and pathogenesis. The E protein contributes to the assembly and release of the virion from the infected cell, following the secretory pathway, which makes it a good indicator of the presence of the virus in tissues. The SARS-CoV-2 E protein is referenced under the reference Gene ID: 43740570.

[0096] By "RBD domain" or "receptor-binding domain" is meant an immunogenic region of a peptide sequence of a virus which binds to an endogenous peptide sequence specific to the ACE2 membrane receptor of a target cell to allow entry of the virus into said target cell. In particular, the RBD domain is present in the S1 subunit of the S protein and located between residues Arg319 and Phe541 of the S protein of viruses of the species SARS-CoV, more particularly SARS CoV-1 and SARS-CoV-2. An example of an RBD domain is represented by SEQ ID NO. 56.

[0097] In the context of the present invention, the terms "therapeutically effective amount" and "prophylactically effective amount" refer to an amount of active ingredient, such as the polypeptide of formula (I), which provides a therapeutic benefit in the treatment, prevention or management of the pathological processes under consideration. The specific amount which is therapeutically effective can be readily determined by a physician and may vary depending on factors such as the type and stage of the pathological processes under consideration, medical history, gender, weight and age of the patient, diet, and the administration of other therapeutic agents.

[0098] In the context of the present invention, the terms "treat", "treatment", "therapy" or "therapeutic" refer to the administration or consumption of an active, i.e., a polypeptide according to the present disclosure, or a pharmaceutical composition comprising such a polypeptide for the purpose of curing, alleviating, reducing, mitigating, or ameliorating a disease or pathological disorder, or one or more associated symptoms, or to prevent or slow the progression of such symptom(s) or disease, or to arrest the development of such symptom(s), or disease or pathological disorder in a statistically significant manner.More particularly, “treat” or “treatment” includes any approach to achieve a beneficial effect or desired outcome with respect to a disease or condition caused by infection with a virus of the species SARS-CoV, in particular SARS-CoV-2, in an individual. Beneficial or desired clinical outcomes may include, but are not limited to, alleviating or improving the condition or disease caused by infection with a virus of the species SARS-CoV, in particular SARS-CoV-2, or one or more symptoms caused by infection with a virus of the species SARS-CoV, in particular SARS-CoV-2; diminishing or reducing the extent of the disease, stabilizing, i.e., not worsening, a disease or condition caused by infection with a virus of the species . SARS-CoV, in particular SARS-CoV-2, or one or more symptoms caused by infection with a virus of the species SARS-CoV, in particular SARS-CoV-2; prevention of a disease or condition caused by infection with a virus of the species SARS-CoV, in particular SARS-CoV-2, or one or more symptoms of such a disease; prevention of the spread of a disease or condition caused by infection with a virus of the species SARS-CoV, in particular SARS-CoV-2, or one or more symptoms of such a disease; slowing down a disease or condition caused by infection with a virus of the species SARS-CoV, in particular SARS-CoV-2, or one or more symptoms of such a disease; the reduction of the recurrence of a disease or condition caused by infection with a virus of the species SARS-CoV, in particular SARS-CoV-2, or of one or more symptoms of such a disease;and the interruption of a disease or condition caused by infection with a virus of the species SARS-CoV, in particular SARS-CoV-2, or one or more symptoms of such a disease. In other words, “treatment” as used herein includes any cure, improvement, reduction, or interruption of a disease or condition caused by infection with a virus of the species SARS-CoV, in particular SARS-CoV-2, or one or more symptoms of such a disease. A “reduction” of a symptom or disease means a decrease in the severity or frequency of the disease or symptom, or the elimination of the disease or symptom. ;

[0099] As used in this description and the claims, the singular forms "a", "an", "the" and "the" include the plurality, unless otherwise explicitly indicated by the context.

[0100] A polypeptide comprising “1 to 100 amino acids” includes a polypeptide comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 and 100 amino acids.

[0101] The term "percentage identity" between two amino acid sequences means the percentage of identical residues between the two sequences to be compared, obtained after optimal alignment, this percentage being purely statistical and the differences between the two sequences being distributed randomly over their length. Optimal alignment of the sequences to be compared can be carried out, in addition to manual comparison, using BLAST P.

[0102] Each minimum numerical limitation given in this description includes any higher numerical limitation, as if such numerical limitations higher were expressly written here. For example, the phrase "at least 72%" includes all numerical values ​​starting from 72, above 72 and up to 100.

[0103] Each numerical range given throughout the description includes each narrower numerical range included within such a wider numerical range, as if these narrower numerical ranges were all expressly written. For example, the expression "between 2 and 5" includes all values ​​from 2 to 5, including 2, 3, 4, and 5.

[0104] All lists indicated in the description, such as, for example, lists of ingredients, are intended and must be interpreted as Markush groups. Thus, all lists can be read and interpreted as elements "selected from the group consisting of" ... list of elements ... "and their combinations and mixtures".

[0105] Reference may be made hereinafter to trade names of components comprising various ingredients used in this specification. The inventors do not intend to be limited to materials under a particular trade name. Equivalent materials (e.g., those obtained from a different source under a different name or reference number) to those indicated herein by a trade name may be substituted and used in the specification herein.

[0106] Polypeptide (HEAT-like alpha-helical repeat proteins (aReps))

[0107] The present invention provides an artificial, isolated or recombinant polypeptide or protein. This polypeptide is capable of binding to the RBD domain of the S protein of viruses of the SARS-CoV species, in particular SARS-CoV-2, and of affecting the entry of the virus into the target cell.

[0108] The present description thus relates to a polypeptide of formula (I)

[0109] NH2-[Nt]-[SBP]z-[Ct]-COOH (I),

[0110] in which: - z is an integer from 1 to 10; - Nt consists of a peptide chosen from SEQ ID NO. 20, SEQ ID NO. 21, SEQ ID NO. 22, SEQ ID NO. 23, SEQ ID NO. 24, SEQ ID NO. 25, SEQ ID NO. 26, SEQ ID NO. 27, SEQ ID NO. 28, SEQ ID NO. 29 SEQ ID NO. 42, SEQ ID NO. 43, SEQ ID NO. 44, SEQ ID NO. 45, SEQ ID NO. 46, SEQ ID NO. 47, SEQ ID NO. 48, SEQ ID NO. 49, SEQ ID NO. 50, SEQ ID NO. 51, SEQ ID NO. 52 and SEQ ID NO. 53; - Ct consists of a peptide having a length of 1 to 100 amino acids; and - SBP consists of a peptide, the variable amino acids of which are identical or different from one SBP to another, of formula (II) NH2 - [SEQ ID NO. 16] - X rX 2-VRX 3-X 4-AAX SALGX 6-I - COOH (II) in which: - X i is an amino acid chosen from A (Alanine), E (Glutamic Acid), T (Threonine), S (Serine), P (Proline), V (Valine), G (Glycine), L (Leucine), K (Lysine), R (Arginine), W (Tryptophan), Y (Tyrosine); - X 2 is an amino acid selected from N (Asparagine), A (Alanine), D (Aspartic Acid), T (Threonine), R (Arginine), S (Serine), Q (Glutamine), Y (Tyrosine), G (Glycine), E (Glutamic Acid), L (Leucine), F (Phenylalanine), W (Tryptophan), N (Asparagine), ; - X 3 is an amino acid selected from I (Isoleucine), Q (Glutamine), R (Arginine), Y (Tyrosine), K (Lysine), T (Threonine), V (Valine), L (Leucine), A (Alanine), F (Phenylalanine), E (Glutamic Acid), S (Serine), M (Methionine), W (Tryptophan); - X 4 is an amino acid chosen from S (Serine), E (Glutamic Acid), T (Threonine), A (Alanine), R (Arginine), G (Glycine), L (Leucine), V (Valine), N (Asparagine); - X 5 is an amino acid selected from A (Alanine), S (Serine), R (Arginine), T (Threonine), N (Asparagine), F (Phenylalanine), V (Valine), G (Glycine), L (Leucine), D (Aspartic Acid), Y (Tyrosine), K (Lysine), R (Arginine), E (Glutamic Acid), W (Tryptophan), N (Asparagine), Q (Glutamine), I (Isoleucine); and - X 6 is an amino acid chosen from K (Lysine), Q (Glutamine), E (Glutamic Acid).

[0111] According to certain other embodiments, the SBP of formula (II), included in the polypeptide of formula (I), consists of:

[0112] - X i is an amino acid chosen from A (Alanine), E (Glutamic Acid), T (Threonine), S (Serine), P (Proline), V (Valine), G (Glycine), L (Leucine), K (Lysine), R (Arginine), W (Tryptophan); - X 2 is an amino acid chosen from N (Asparagine), A (Alanine), D (Aspartic Acid), T (Threonine), R (Arginine), S (Serine), Q (Glutamine), Y (Tyrosine), G (Glycine), E (Glutamic Acid), L (Leucine), F (Phenylalanine), W (Tryptophan); - X 3 is an amino acid chosen from I (Isoleucine), Q (Glutamine), R (Arginine), Y (Tyrosine), K (Lysine), T (Threonine), V (Valine), L (Leucine), A (Alanine), F (Phenylalanine); - X 4 is an amino acid chosen from S (Serine), E (Glutamic Acid), T (Threonine), A (Alanine), R (Arginine), G (Glycine), L (Leucine), V (Valine); - X 5 is an amino acid selected from A (Alanine), S (Serine), R (Arginine), T (Threonine), N (Asparagine), F (Phenylalanine), V (Valine), G (Glycine), L (Leucine), D (Aspartic Acid), Y (Tyrosine), K (Lysine), R (Arginine), E (Glutamic Acid), W (Tryptophan), N (Asparagine), Q (Glutamine); and - X 6 is an amino acid chosen from K (Lysine), Q (Glutamine), E (Glutamic Acid).

[0113] According to some embodiments, z may be an integer from 3 to 8.

[0114] According to certain embodiments, Nt can be chosen from the acid sequences amines SEQ ID NO. 20, SEQ ID NO. 21, SEQ ID NO. 22, SEQ ID NO. 23, SEQ ID NO. 24, SEQ ID NO. 25, SEQ ID NO. 26, SEQ ID NO. 27, SEQ ID NO. 28 and SEQ ID NO. 29.

[0115] According to certain preferred embodiments, Nt may be selected from the amino acid sequences SEQ ID NO. 20, SEQ ID NO. 26, and SEQ ID NO. 29.

[0116] In particular, Nt consists of an amino acid sequence SEQ ID NO. 20.

[0117] In some embodiments, Ct comprises 1;2;3;4;5;6;7;8;9;10; 11; 12; 13; 14; 15; 16; 17; 18; 19; 20; 21; 22; 23; 24; 25; 26; 27; 28; 29; 30; 31; 32; 33; 34; 35; 36; 37; 38; 39; 40; 41; 42; 43; 44; 45; 46; 47; 48; 49; 50; 51; 52; 53; 54; 55; 56; 57; 58; 59; 60; 61; 62; 63; 64; 65; 66; 67; 68; 69; 70; 71; 72; 73; 74; 75; 76; 77; 78; 79; 80; 81; 82; 83; 84; 85; 86; 87; 88; 89; 90; 91; 92; 93; 94; 95; 96; 97; 98; 99; or 100 amino acids. In some embodiments, the Ct portion of the polypeptide of the present disclosure comprises less than 70 amino acids. In some embodiments, the Ct portion of the polypeptide of the present disclosure comprises less than 50 amino acids. In some embodiments, the Ct portion of the polypeptide of the present disclosure comprises less than 40 amino acids. In some embodiments, the Ct portion of the polypeptide of the present disclosure comprises 36 amino acids.

[0118] According to certain preferred embodiments, Ct consists of a peptide having a length of 1 to 50 amino acids.

[0119] According to certain preferred embodiments, Ct consists of a peptide having a length of 1 to 36 amino acids.

[0120] In particular, Ct consists of an amino acid sequence SEQ ID NO. 18.

[0121] According to certain preferred embodiments, the SBP of formula (II), included in the polypeptide of formula (I), comprises:

[0122] - X i is an amino acid chosen from A (Alanine), E (Glutamic Acid), S (Serine), P (Proline), G (Glycine), R (Arginine), W (Tryptophan); - X 2 is an amino acid selected from N (Asparagine), A (Alanine), D (Aspartic Acid), R (Arginine), S (Serine), Y (Tyrosine), E (Glutamic Acid), L (Leucine), F (Phenylalanine); - X 3 is an amino acid chosen from I (Isoleucine), Q (Glutamine), R (Arginine), K (Lysine), V (Valine), L (Leucine), A (Alanine), F (Phenylalanine); - X 4 is an amino acid chosen from S (Serine), E (Glutamic Acid), A (Alanine), R (Arginine), N (Asparagine); - X 5 is an amino acid selected from A (Alanine), S (Serine), R (Arginine), T (Threonine), N (Asparagine), G (Glycine), L (Leucine), K (Lysine), W (Tryptophan); and - X 6 is an amino acid chosen from K (Lysine), Q (Glutamine), E (Glutamic Acid).

[0123] According to certain embodiments, the polypeptide of formula (I) can be chosen from SEQ ID NO. 1, SEQ ID NO. 2, SEQ ID NO. 3, SEQ ID NO. 4, SEQ ID NO. 5, SEQ ID NO. 6, SEQ ID NO. 7, SEQ ID NO. 8, SEQ ID NO. 9, SEQ ID NO. 10, SEQ ID NO. 30, SEQ ID NO. 31, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 34, SEQ ID NO. 35, SEQ ID NO. 36, SEQ ID NO. 37, SEQ ID NO. 38, SEQ ID NO. 39, SEQ ID NO. 40 and SEQ ID NO.41.

[0124] According to certain preferred embodiments, the polypeptide of formula (I) may be selected from SEQ ID NO. 1, SEQ ID NO. 2, SEQ ID NO. 3, SEQ ID NO. 4, SEQ ID NO. 5, SEQ ID NO. 6, SEQ ID NO. 7, SEQ ID NO. 8, SEQ ID NO. 9 and SEQ ID NO. 10.

[0125] According to certain embodiments, the polypeptide of formula (I) does not consist of a peptide of SEQ ID NO. 8.

[0126] According to certain other preferred embodiments, the polypeptide of formula (I) may be chosen from the peptides of sequence SEQ ID NO. 1, SEQ ID NO. 7 and SEQ ID NO. 10. Composite polypeptide

[0127] According to another of its objects, the present description relates to a composite polypeptide comprising a plurality of polypeptides of formula (I) as described herein.

[0128] According to certain embodiments, a composite polypeptide according to the present disclosure consists of a dimer or a trimer of a polypeptide of formula (I) of the present disclosure.

[0129] The term "dimer" means a protein composed of two polypeptides of formula (I) which may be either identical in the case of a homodimer or different in the case of a heterodimer. The two polypeptides of formula (I) may be linked by a linker peptide.

[0130] The term “trimer” means a protein composed of three polypeptides of formula (I) which may be either identical in the case of a homotrimer, or different in the case of a heterotrimer.

[0131] The inventors have demonstrated that the homologous or heterologous multimerization of a polypeptide of formula (I) makes it possible, without wishing to be bound by any theory, to increase the neutralizing activity of the polypeptide of formula (I).

[0132] The three polypeptides of formula (I) can be linked by a linker peptide.

[0133] According to certain embodiments, several consecutive polypeptides of formula (I) included in a composite polypeptide according to the present description are indirectly linked to each other via a linker peptide, i.e. the consecutive polypeptides of formula (I) are separated from each other by a linker peptide.

[0134] According to certain embodiments, several consecutive polypeptides of formula (I) included in a composite polypeptide according to the present description are linked directly to each other, therefore in the absence of a linking peptide.

[0135] According to certain embodiments of a composite polypeptide, the polypeptides of formula (I) are linked non-covalently or covalently.

[0136] According to certain embodiments of a composite polypeptide, the polypeptides of formula (I) are covalently linked by a linker peptide.

[0137] In particular, a composite polypeptide comprising a polypeptide dimer of formula (I) consists of a composite polypeptide of construction (Chem 1) such that:

[0138] [Chem.l] [polypeptide of formula (l)]a - [linker peptide]x - [polypeptide of formula (I)]b

[0139] in which: - the [polypeptide of formula (I)]a and the [polypeptide of formula (I)]b, identical or different, are chosen from the different embodiments of the polypeptide of formula (I), as defined in the present description, - - X is an integer equal to 0 or 1; and

[0140] - the [linker peptide] comprises a polypeptide sequence of 1 to 100 acids amino acids, preferably from 1 to 50 amino acids, more preferably the [linker peptide] consists of a peptide of SEQ ID NO. 19, wherein, preferably, the [polypeptide of formula (I)]a, the [linker peptide] and the [polypeptide of formula (I)]b are covalently linked.

[0141] According to some embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein the [polypeptide of formula (I)]a and the [polypeptide of formula (I)]b are the same or different.

[0142] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 1, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 1.

[0143] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 1, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 2.

[0144] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 1, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 3.

[0145] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 1, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 4.

[0146] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 1, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 5.

[0147] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 1, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 6.

[0148] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 1, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 7.

[0149] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 1, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 8.

[0150] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 1, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 9.

[0151] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 1, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 10.

[0152] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 1, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 54.

[0153] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 2, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 2.

[0154] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 2, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 3.

[0155] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 2, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 4.

[0156] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 2, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 5.

[0157] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 2, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 6.

[0158] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 2, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 7.

[0159] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 2, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 8.

[0160] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 2, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 9.

[0161] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 2, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 10.

[0162] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 2, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 54.

[0163] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 3, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 3.

[0164] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 3, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 4.

[0165] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 3, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 5.

[0166] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 3, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 6.

[0167] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 3, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 7.

[0168] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 3, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 8.

[0169] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 3, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 9.

[0170] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 3, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 10.

[0171] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 3, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 54.

[0172] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 4, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 4.

[0173] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 4, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 5.

[0174] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 4, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 6.

[0175] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 4, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 7.

[0176] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 4, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 8.

[0177] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 4, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 9.

[0178] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 4, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 10.

[0179] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 4, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 54.

[0180] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 5, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 5.

[0181] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 5, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 6.

[0182] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 5, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 7.

[0183] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 5, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 8.

[0184] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 5, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 9.

[0185] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 5, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 10.

[0186] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 5, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 54.

[0187] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 6, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 6.

[0188] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 6, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 7.

[0189] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 6, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 8.

[0190] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 6, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 9.

[0191] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 6, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 10.

[0192] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 6, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 54.

[0193] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 7, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 7.

[0194] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 7, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 8.

[0195] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 7, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 9.

[0196] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 7, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 10.

[0197] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 7, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 54.

[0198] According to some embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 8, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 8.

[0199] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 8, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 9.

[0200] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 8, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 10.

[0201] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 8, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 54.

[0202] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 9, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 9.

[0203] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 9, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 10.

[0204] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 9, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 54.

[0205] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 10, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 10.

[0206] According to certain embodiments, the composite polypeptide consists of a polypeptide of construct (Chem 1), wherein when the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 10, the [polypeptide of formula (I)]consists of a peptide of SEQ ID NO. 54.

[0207] According to certain embodiments, the [polypeptide of formula (I)]a and the [polypeptide of formula (I)]b, of a composite polypeptide consisting of a polypeptide of construct (Chem 1) do not consist of peptides of SEQ ID NO. 8.

[0208] According to certain embodiments, the composite polypeptide may comprise a polypeptide of formula (I) preferably non-covalently linked by its N-terminal amino acid residue to a peptide of sequence SEQ ID NO. 54.

[0209] The peptide of sequence SEQ ID NO. 54 is called “foldon” in the present description.

[0210] The inventors have demonstrated that the homologous multimerization of a polypeptide of formula (I) with a “foldon” sequence makes it possible, without wishing to be bound by any theory, to increase the neutralizing activity of the polypeptide of formula (I) by allowing better multimerization of the polypeptide of formula (I).

[0211] In particular, a composite polypeptide may consist of a composite polypeptide of construction (Chem 2) such that:

[0212] [Chem.2] [polypeptide of formula (l)] a - [SEQ ID NO. 54]b

[0213] in which: - the [polypeptide of formula (I)]a is chosen from the different embodiments of the polypeptide of formula (I), as defined in the present description,

[0214] wherein, preferably, the [polypeptide of formula (I)]a and [SEQ ID NO. 54] are non-covalently linked.

[0215] According to certain preferred embodiments, the composite polypeptide is selected from the peptides of sequence SEQ ID NO. 12, SEQ ID NO. 13, SEQ ID NO. 14 and SEQ ID NO. 15.

[0216] According to certain particular embodiments, a composite polypeptide may comprise a polypeptide trimer of formula (I) consisting of a composite polypeptide of construction (Chem 3) such that:

[0217] [Chem.3] [polypeptide of formula (1 / 2 - [linking peptide_1] - [polypeptide of formula (1)]b— [linking peptide_2] - [polypeptide of formula {1)]c

[0218] in which: - the [polypeptide of formula (I)]a, [polypeptide of formula (I)]b, and the [polypeptide of formula (I)]c are chosen from the different embodiments of the polypeptide of formula (I), as defined in the present description, and

[0219] - [linker peptide_l] and [linker peptide_2], identical or different, each comprise a peptide of 1 to 100 amino acids, preferably 1 to 50 amino acids. In some embodiments, the [linker peptide_1] and / or the [linker peptide_2] consists of a peptide of sequence SEQ ID NO. 19, wherein, preferably, the [polypeptide of formula (I)]a, the [linker peptide_1], the [polypeptide of formula (I)]b, the [linker peptide_2], and the [polypeptide of formula (I)]c are covalently linked.

[0220] In some embodiments, the composite polypeptide of the present disclosure may consist of a polypeptide of construct (Chem 2), wherein [polypeptide of formula (I)]a, [polypeptide of formula (I)]b and [polypeptide of formula (I)]c are the same or different. In some embodiments, [polypeptide of formula (I)]a, [polypeptide of formula (I)]b and [polypeptide of formula (I)]c are the same. In some embodiments, [polypeptide of formula (I)]a, [polypeptide of formula (I)]b and [polypeptide of formula (I)]c are all different from each other. In some embodiments, two polypeptides of [polypeptide of formula (I)]a, [polypeptide of formula (I)]b and [polypeptide of formula (I)]c are identical, the third polypeptide of formula (I) being different from the other two.

[0221] According to certain particular embodiments, the composite polypeptide may consist of a polypeptide of construct (Chem 2), in which the [polypeptide of formula (I)]a, the [polypeptide of formula (I)]b and the [polypeptide of formula (I)]c consist of a peptide of sequence SEQ ID NO. 1.

[0222] According to certain particular embodiments, the composite polypeptide may consist of a polypeptide of construct (Chem 2), in which the [polypeptide of formula (I)]a, the [polypeptide of formula (I)]b and the [polypeptide of formula (I)]c consist of a peptide of sequence SEQ ID NO. 2.

[0223] According to certain particular embodiments, the composite polypeptide may consist of a polypeptide of construct (Chem 2), in which the [polypeptide of formula (I)]a, the [polypeptide of formula (I)]b and the [polypeptide of formula (I)]c consist of a peptide of sequence SEQ ID NO. 3.

[0224] According to certain particular embodiments, the composite polypeptide may consist of a polypeptide of construct (Chem 2), in which the [polypeptide of formula (I)]a, the [polypeptide of formula (I)]b and the [polypeptide of formula (I)]c consist of a peptide of sequence SEQ ID NO. 4.

[0225] According to certain particular embodiments, the composite polypeptide may consist of a polypeptide of construct (Chem 2), in which the [polypeptide of formula (I)]a, the [polypeptide of formula (I)]b and the [polypeptide of formula (I)]c consist of a peptide of sequence SEQ ID NO. 5.

[0226] According to certain particular embodiments, the composite polypeptide may consist of a polypeptide of construct (Chem 2), in which the [polypeptide of formula (I)]a, the [polypeptide of formula (I)]b and the [polypeptide of formula (I)]c consist of a peptide of sequence SEQ ID NO. 6.

[0227] According to certain particular embodiments, the polypeptide may consist of a polypeptide of construct (Chem 2), in which the [polypeptide of formula (I)]a, the [polypeptide of formula (I)]b and the [polypeptide of formula (I)]c consist of a peptide of sequence SEQ ID NO. 7.

[0228] According to certain particular embodiments, the composite polypeptide may consist of a polypeptide of construct (Chem 2), in which the [polypeptide of formula (I)]a, the [polypeptide of formula (I)]b and the [polypeptide of formula (I)]c consist of a peptide of sequence SEQ ID NO. 8.

[0229] According to certain particular embodiments, the composite polypeptide may consist of a polypeptide of construct (Chem 2), in which the [polypeptide of formula (I)]a, the [polypeptide of formula (I)]b and the [polypeptide of formula (I)]c consist of a peptide of sequence SEQ ID NO. 9.

[0230] According to certain particular embodiments, the composite polypeptide may consist of a polypeptide of construct (Chem 2), in which the [polypeptide of formula (I)]a, the [polypeptide of formula (I)]b and the [polypeptide of formula (I)]c consist of a peptide of sequence SEQ ID NO. 10.

[0231] According to certain particular embodiments, the composite polypeptide of the present description may be chosen from the peptides of sequence SEQ ID NO. 11, SEQ ID NO. 12, SEQ ID NO. 13, SEQ ID NO. 14 and SEQ ID NO. 15. Pharmaceutical compositions

[0232] Also provided are pharmaceutical compositions, comprising a polypeptide of formula (I) according to the present description and / or a polypeptide of formula (I) in a dimerized or trimerized form, formulated with a pharmacologically or pharmaceutically acceptable excipient or carrier.

[0233] These pharmaceutical compositions may comprise one or more combinations of polypeptides of formula (I) according to the present disclosure (e.g., two or more different ones). For example, a pharmaceutical composition described herein may comprise a combination of polypeptides of formula (I) that bind to different epitopes of a target virus.

[0234] In some cases, the pharmaceutical composition comprises at least about 1 mg / ml, 5 mg / ml, 10 mg / ml, 50 mg / ml, 100 mg / ml, 150 mg / ml, 200 mg / ml, 1-300 mg / ml or about 100-300 mg / ml of polypeptide of formula (I) and / or polypeptide of formula (I) in a dimerized or trimerized form.

[0235] The pharmaceutical compositions described herein may also be administered in combination therapy, i.e., in combination with other agents. For example, the combination therapy may include a polypeptide of formula (I) described herein in combination with at least one antiviral agent and / or an antipathogenic agent.

[0236] The pharmaceutical compositions described herein may include one or more pharmaceutically acceptable salts. By "pharmaceutically acceptable salt" is meant a salt that retains the desired biological activity of the parent compound and does not impart undesirable toxic effects. Acid addition salts and base addition salts are examples of such salts. Acid addition salts include non-toxic inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, and aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanes. Salts derived from non-toxic organic acids such as aliphatic and aromatic acids, aromatic acids, sulfonic acids are included.Base addition salts include, for example, alkaline earth metals such as sodium, potassium, magnesium and calcium, as well as N,N'-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine and others. Salts derived from toxic organic amines are included.

[0237] The pharmaceutical compositions described herein may also include a pharmaceutically acceptable antioxidant. Examples of pharmaceutically acceptable antioxidants include (1) water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc. (2) oil-soluble antioxidants, oxidizing agents such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelators such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like are included.

[0238] Examples of suitable aqueous or non-aqueous carriers that may be used in the pharmaceutical compositions described herein include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Suitable fluidity may be maintained, for example, by maintaining the required particle size in the case of dispersion and by using surfactants.

[0239] These pharmaceutical compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the presence of microorganisms can be ensured both by the sterilization methods described above and by the inclusion of various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid and others. It may also be desirable to include in the pharmaceutical composition isotonic agents such as sugars, sodium chloride. In addition, the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin, can delay the absorption of injectable pharmaceutical forms.

[0240] Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. The use of such carriers and agents for pharmaceutically active substances is well known in the art. Except to the extent that a conventional medium or agent is incompatible with the active ingredient, its use in the pharmaceutical compositions described herein is contemplated. Additional active substances may also be incorporated into the compositions.

[0241] A pharmaceutical composition must generally be sterile and stable under the conditions of manufacture and storage. The composition may be formulated as a solution, microemulsion, solution, microemulsion, liposome, or other ordered structure suitable for high drug concentration. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersion, and by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol and sorbitol, or sodium chloride in the composition.Delayed absorption of injectable compositions may be caused by the inclusion in the composition of an agent that delays absorption, for example, monostearate salts and gelatin.

[0242] Sterile injectable solutions may be prepared by including the active compound, i.e., polypeptides of formula (I) described herein, in the required amount in a suitable solvent, optionally with one or a combination of the ingredients listed above, and then sterilizing by microfiltration. In general, the dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the other necessary ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred method of preparation is a vacuum drying method, in which a powder of the active ingredient plus any other desired ingredient is produced from the previously sterilized filtered solution, and lyophilization.

[0243] The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form may vary depending on the subject being treated and the particular mode of administration. The amount of active ingredient, i.e., polypeptides of formula (I) described herein, that can be combined with a carrier material to produce a single dosage form will generally be the amount of the composition that produces a therapeutic effect.

[0244] According to certain embodiments, the amount of active ingredient, i.e. polypeptides of formula (I) described herein, is from about 0.01% to about 99% relative to the amount of final composition, preferably from about 0.1% to about 70% relative to the amount of final composition, most of the time combined with a pharmaceutically acceptable carrier.

[0245] Dosage regimens are adjusted to achieve the desired optimal response (e.g., therapeutic response). In some embodiments, a single bolus administration is possible and multiple divided doses may be administered over an extended period, or the dose may be reduced or increased proportionally as indicated in an imminent treatment situation. Preferably, the formulation of parenteral compositions is in unit dosage form, particularly for ease of administration and uniformity of dosing.

[0246] The term "parenteral administration" means modes of administration other than enteral and topical administration, generally by injection, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, intranasal, subcutaneous, epidermal, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrastemial, including, but not limited to, injections and infusions.

[0247] In some embodiments, a unit dosage form refers to a unit that is physically suitable as a single dose for the individual to be treated; each unit, in combination with the required pharmaceutical carrier, produces the desired therapeutic effect.

[0248] According to certain embodiments, for the administration of polypeptides of formula (I), the dosage varies between about 0.0001 and 100 mg, more generally between 0.01 and 5 mg per kg of body weight of the host. For example, the dosage is between 0.3 mg / kg body weight, 1 mg / kg body weight, 3 mg / kg body weight, 5 mg / kg body weight or 10 mg / kg body weight, or 1-10 mg / kg.

[0249] According to some embodiments, a treatment regimen may be once daily, twice daily, three times daily, or four times daily administration over a 7-day period.

[0250] According to certain embodiments, dosage regimens for administering a pharmaceutical composition according to the present disclosure comprise 1 mg / kg body weight or 3 mg / kg body weight by intranasal, intraperitoneal or intravenous administration. In particular, the composition is administered (i) 3 times daily for 7 days, followed by (ii) 1 time daily for 7 days.

[0251] According to certain embodiments, dosage regimens for administering a pharmaceutical composition according to the present disclosure comprise 15 mg / 0.1 ml or 20 mg / 0.1 ml by nasal administration. In particular, the composition is administered (i) 3 times daily in each nostril for 7 days, followed by (ii) 1 time daily in each nostril for 7 days.

[0252] In some embodiments, the pharmaceutical composition is used for prophylactic or therapeutic treatment. The dosage and frequency of administration may vary depending on whether the treatment is prophylactic or therapeutic. In prophylactic applications, relatively low doses are administered over long periods at relatively infrequent intervals. Some patients continue to receive treatment for the remainder of their lives. In therapeutic applications, relatively high doses at relatively short intervals may be required until disease progression is reduced or halted, preferably until the patient shows partial or complete improvement in disease symptoms. Thereafter, the patient may be administered a prophylactic regimen.

[0253] The actual dosage levels of the active ingredients of the pharmaceutical compositions according to the present disclosure are non-toxic to the patient in order to obtain the desired therapeutic response for the individual, in particular the composition and method of administration. It is possible to vary them to obtain an effective amount of active ingredient. The dosage level selected depends on the particular composition used, or the activity of its ester, salt or amide, the route of administration, the time of administration, the rate of elimination of the particular compound used, the duration of treatment, other drugs, compounds and / or substances used in combination with a particular composition, the age, sex, weight, condition, general health and medical history of the individual to be treated, as well as similar factors well known in the art medical. The dosage level may also vary depending on various pharmacokinetic factors.

[0254] In some embodiments, a therapeutically effective dose may prevent or delay the onset of a disease or condition related to infection with a virus of the SARS-CoV species, particularly SARS-CoV-2. For example, laboratory tests used to diagnose disease include chemistry, hematology, serology, and radiology. Accordingly, clinical or biochemical assays that monitor any of the above may be used to determine whether a particular treatment is a therapeutically effective dose for treating the disease. One skilled in the art may determine such amounts based on factors such as the size of the individual, the severity of the individual's symptoms, and the particular composition or route of administration chosen.

[0255] The pharmaceutical compositions according to the present disclosure may be administered according to one or more methods known in the art, by one or more routes of administration. As will be appreciated by those skilled in the art, the route of administration and / or the mode of administration will vary depending on the desired result.

[0256] According to certain preferred embodiments, the pharmaceutical compositions according to the present description or polypeptides of formula (I) according to the present description can be administered orally, parenterally, by inhalation, by aerosol, by spray, topically, rectally, nasally, buccally, vaginally, ophthalmologically or via an implanted reservoir.

[0257] Preferably, the pharmaceutical compositions according to the present description or the polypeptides of formula (I) according to the present description are administered orally, intraperitoneally, intravenously, intranasally or by inhalation. The sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.

[0258] According to certain particular embodiments, the pharmaceutical compositions according to the present description can also be administered by nasal aerosol or by inhalation.

[0259] All of the characteristics and particular modes relating to the polypeptide of formula (I) and to the pharmaceutical composition comprising it also apply to the uses and methods targeted according to the present description. Uses

[0260] As indicated above, the polypeptide of formula (I) according to the present description or a pharmaceutical composition comprising said polypeptide of formula (I) can be used as a medicament.

[0261] Thus, according to certain embodiments, the present description relates to a polypeptide of formula (I) or a pharmaceutical composition comprising a polypeptide of formula (I) according to the present description for use as a medicament.

[0262] According to a particular embodiment, the present description relates to a polypeptide of formula (I) or a pharmaceutical composition comprising a polypeptide of formula (I): NH2-[Nt]-[SBP]z-[Ct]-COOH (I), in which: - z is an integer from 1 to 10; - Nt consists of a peptide chosen from SEQ ID NO. 20, SEQ ID NO. 21, SEQ ID NO. 22, SEQ ID NO. 23, SEQ ID NO. 24, SEQ ID NO. 25, SEQ ID NO. 26, SEQ ID NO. 27, SEQ ID NO. 28, SEQ ID NO. 29 SEQ ID NO. 42, SEQ ID NO. 43, SEQ ID NO. 44, SEQ ID NO. 45, SEQ ID NO. 46, SEQ ID NO. 47, SEQ ID NO. 48, SEQ ID NO. 49, SEQ ID NO. 50, SEQ ID NO. 51, SEQ ID NO. 52 and SEQ ID NO. 53; - Ct consists of a peptide having a length of 1 to 100 amino acids; and - SBP consists of a peptide, whose variable amino acids are identical or different from one SBP to another, of formula (II) NH2 - [SEQ ID NO. 16] - X rX 2-VRX 3-X 4-AAX SALGX 6-I - COOH (II) in which: - X i is an amino acid chosen from A (Alanine), E (Glutamic Acid), T (Threonine), S (Serine), P (Proline), V (Valine), G (Glycine), L (Leucine), K (Lysine), R (Arginine), W (Tryptophan), Y (Tyrosine); - X 2 is an amino acid selected from N (Asparagine), A (Alanine), D (Aspartic Acid), T (Threonine), R (Arginine), S (Serine), Q (Glutamine), Y (Tyrosine), G (Glycine), E (Glutamic Acid), L (Leucine), F (Phenylalanine), W (Tryptophan), N (Asparagine), ; - X 3 is an amino acid selected from I (Isoleucine), Q (Glutamine), R (Arginine), Y (Tyrosine), K (Lysine), T (Threonine), V (Valine), L (Leucine), A (Alanine), F (Phenylalanine), E (Glutamic Acid), S (Serine), M (Methionine), W (Tryptophan); - X 4 is an amino acid chosen from S (Serine), E (Glutamic Acid), T (Threonine), A (Alanine), R (Arginine), G (Glycine), L (Leucine), V (Valine), N (Asparagine); - X 5 is an amino acid selected from A (Alanine), S (Serine), R (Arginine), T (Threonine), N (Asparagine), F (Phenylalanine), V (Valine), G (Glycine), L (Leucine), D (Aspartic Acid), Y (Tyrosine), K (Lysine), R (Arginine), E (Glutamic Acid), W (Tryptophan), N (Asparagine), Q (Glutamine), I (Isoleucine); and - X 6 is an amino acid selected from K (Lysine), Q (Glutamine), E (Glutamic Acid), for use as a medicament.

[0263] According to another subject of the present invention, a pharmaceutical composition according to the present description or a polypeptide of formula (I) according to the present description is in particular used in a therapeutic method for treating and / or preventing a disease or condition caused by an infection by a virus of the species SARS-CoV, in particular SARS-CoV-2, in an individual in need thereof.

[0264] According to certain preferred embodiments, a pharmaceutical composition comprising a polypeptide of formula (I) according to the present description or a polypeptide of formula (I) according to the present description is used in a therapeutic method for treating and / or preventing a disease or condition caused by infection with a virus of the species SARS-CoV, in particular SARS-CoV-2 in an individual in need thereof.

[0265] According to some embodiments, a condition caused by infection with a virus of the species SARS-CoV, in particular SARS-CoV-2, may be a severe respiratory distress syndrome, a cardiovascular condition, a vascular condition, a gastrointestinal condition, or a neurological condition.

[0266] According to some embodiments, a disease caused by infection with a virus of the species SARS-CoV, in particular SARS-CoV-2, may be COVID-19.

[0267] According to certain preferred embodiments, a pharmaceutical composition comprising a polypeptide of formula (I) according to the present description or a polypeptide of formula (I) according to the present description for use in a method of treating or preventing an infection by a virus of the species SARS-CoV, in particular SARS-CoV-2, is intended to reduce inflammation associated with infection by the virus.

[0268] According to certain preferred embodiments, a pharmaceutical composition comprising a polypeptide of formula (I) according to the present description or a polypeptide of formula (I) according to the present description for use in a method of treating or preventing an infection by a virus of the species SARS-CoV, in particular SARS-CoV-2, is intended to reduce the viral load of the virus.

[0269] According to certain preferred embodiments, a pharmaceutical composition comprising a polypeptide of formula (I) according to the present description or a polypeptide of formula (I) according to the present description may be particularly suitable for use in a method of treating or preventing an infectious disease, in particular for inhibiting or destroying cells infected with a virus of the species SARS-CoV, in particular infectious SARS-CoV-2.

[0270] According to one embodiment, an infectious disease may be a respiratory infectious disease called COVID-19.

[0271] Also provided is a method of treating and / or preventing a disease or condition caused by infection with a virus of the species SARS-CoV, in particular SARS-CoV-2, in an individual in need thereof, comprising administering to the individual a polypeptide according to the present description or a pharmaceutical composition comprising a polypeptide according to the present description.

[0272] In addition to the therapies according to the present description, the polypeptides of formula (I) or pharmaceutical compositions comprising these polypeptides can also be used in combination with another therapy using antivirals or antipathogens. For example, the polypeptides of formula (I) can be administered in combination with molecules targeting enzymes, such as proteases, encoded by the SARS-CoV-2 genome or viral RNA polymerase.

[0273] The use of a polypeptide according to the present description is also provided for obtaining a medicament intended to treat and / or prevent a disease or condition caused by an infection by a virus of the SARS-CoV species, in particular SARS-CoV-2, in an individual in need thereof. Examples Example 1: Materials and methods

[0274] 1. Recombinant production of the SI and RBD domains of the SARS- CoV-2

[0275] The S1 subunit consisting of the first 681 amino acids of the S protein was fused at its C-terminus to a histidine tag (8xHis) for expression in HEK-293T cells and purification (provided by CreativeDiagnostics). A DNA segment encoding the RBD domain (highlighted in bold in SEQ ID NO. 55) placed downstream of a segment encoding a signal peptide and upstream of a sequence encoding a His-Tag was expressed by transient transfection of HEK-293T cells using the pCI expression vector.

[0276] The RBD domain (SEQ ID NO. 56, highlighted in bold in SEQ ID NO. 57) is positioned between a signal peptide to ensure its translocation and a histidine tag (SEQ ID NO. 57).

[0277] Purification of the RBD domain was performed by Ni-NTA affinity chromatography followed by gel filtration and concentration. Then, 0.3 mg of SI and 5 mg of RBD domain were used for screening of aReps. 2. Expression and purification of aReps proteins

[0278] The aRep genes corresponding to proteins with high binding affinity to the S1 subunit and the RBD domain were subcloned using BamHI-HindIII restriction sites in the pQE81 plasmid for amplification. The pQE81 derivatives were used for transformation of Rosetta E. coli cells and the resulting clones were cultured at 37°C in 2XYT broth supplemented with ampicillin (100 μg / ml) and chloramphenicol (40 μg / ml) with shaking. When the absorbance at 600 nm reached 0.8 to 1, the expression of the aRep protein was induced by adding 0.5 to 1 mM IPTG, and the cells were then incubated for 4 to 12 hours at 28°C or 37°C with shaking.

[0279] Then, the bacteria were pelleted by centrifugation (5,000 xg for 30 minutes at 4°C), and the bacterial cell pellets were resuspended in 200 mM NaCl, 20 rnM Tris pH 7.4 to 8, depending on the isoelectric point of the protein, containing a protease inhibitor cocktail (Roche Diagnostics GmbH), and then lysed by sonication in ice (5 times x (30 s rest and 30 s sonication at approximately 40% amplitude) using a Q700 QSONICA sonicator). The bacterial cell lysates were clarified by centrifugation at 10,000 xg for 30 minutes at 4°C.

[0280] Soluble recombinant aReps proteins, tagged 6xHis, were purified by affinity chromatography on HisTrap columns (GE Healthcare Life Sciences) and eluted by an imidazole buffer gradient (equilibration buffer: 40 mM Imidazole, 300 mM NaCl, 20 mM Tris pH8, Elution buffer: IM Imidazole, 300 mM NaCl, 20 mM Tris pH 8). The fractions of interest were pooled and injected into a Superdex S200 gel filtration previously equilibrated with PBS.

[0281] The resulting fractions were analyzed by SDS-PAGE and the fractions containing the purified aReps were pooled and frozen at -20°C.

[0282] 3. Determination of the binding affinities of aReps

[0283] Binding kinetics experiments were performed on an Octet system (Octet RED96) (ForteBio, Molecular Devices) in 8-channel mode.

[0284] His-tagged SARS-CoV-2 RBD or SI protein was loaded onto HislK biosensors (Pall ForteBio) up to a loading threshold of 1 nm. After a basal step in assay buffer (PBS [pH 7.4], 0.1% bovine serum albumin, 0.05% Tween 20), ligand-loaded sensors were immersed in known concentrations of aReps for an association phase followed by a dissociation phase induced by replacing the aReps-containing solutions with buffer alone. The association and dissociation curves were roughly fitted to a 1:1 binding model. The binding curves were fitted using the "association then dissociation" equation in GraphPad Prism to calculate the binding constant dissociation (KD). The lower the KD value, the higher the binding affinity between the aReps and its target, RBD or SI.

[0285] 4. Neutralization tests of SARS-CoV-2 pseudotypes by aReps

[0286] MLV particles pseudotyped with SARS-CoV-2 S protein (SARS-CoV-2PP) and VSV G protein (control) and driving Firefly luciferase gene expression were produced as previously described (Millet and Whittaker, 2016, Bio Protoc. 6:e2035), with a plasmid encoding a human codon-optimized sequence of the S gene (Genebank accession number: MN908947) or VSV G gene (control) (Sun et al. J Biol Chem. 2008 Mar 7; 283(10):6418-27). Supernatants containing the pseudotyped particles were harvested at 48 h, 72 h, and 96 h post-transfection, pooled, and filtered through 0.45 µm pore membranes. The day before transduction, 50,000 HEK293T cells expressing ACE2 were placed in each well of a 24-well plate. The quantity of pseudotyped particles used per well was previously established to obtain a signal of approximately 105 (in arbitrary fluorescence units) three days after transduction.Ten-fold dilutions of alphaReps were made in complete medium (DMEM + 2% FBS + PSG) and were preincubated for 1 h at room temperature with SARS-CoV-2PP in a final volume of 200 pL. These mixtures were deposited in each of the wells containing HEK293T-ACE2 cells to perform transduction. Three days after transduction, cells were trypsinized and luciferase activity was measured as indicated by the manufacturer (Promega) on a TECAN Infinité M200Pro instrument. Neutralization titers were defined as the dilution of aRep that results in a 50% decrease in infectivity. Retroviral particles pseudotyped with vesicular stomatitis virus glycoprotein G (VSVpp) were used to control neutralization specificity.

[0287] 5. Neutralization test of SARS-CoV-2 and its mutants by aReps

[0288] SARS-CoV-2, isolate France / IDF0372 / 2020, was provided by the National Reference Center for Respiratory Viruses hosted by the Institut Pasteur (Paris, France). Mutant neutralization experiments were performed with pseudotypes of S protein mutants representative of the RBD of the different variants tested. Viral stocks were prepared by propagation in Vero E6 cells in Dulbecco's modified Eagle's medium (DMEM) supplemented with 2% (v / v) fetal bovine serum (FBS, Invitrogen). Viral titers were determined by the plaque assay. All plaque assays involving live SARS-CoV-2 were performed in an approved laboratory, in biosafety level 3 (BSL-3) containment. All experiments were performed in at least three biologically independent replicates.

[0289] Neutralization assays of infectious SARS-CoV-2 were performed on Vero E6 cells (CRL-1586, ATCC) as follows. Briefly, aReps were serially diluted three-fold or ten-fold in DMEM containing 2% (v / v) FBS (Invitrogen) and mixed with 104 plaque-forming units (PFU) of SARS-CoV-2 for one hour at 37°C, 5% CO2. The mixture was then used to inoculate Vero E6 cells seeded in P96 well plates, for one hour at 37°C, 5% CO2. Control conditions were tested with cells alone (medium alone) and virus alone in medium. The cells were incubated for an additional 3 days. Cell viability was measured by removing 100 µl of supernatant from all wells and adding 100 µl of CellTiter-Glo reagent as described in the manufacturer's protocol (CellTiter-Glo Luminescent Cell Viability Assay).Luminescence was read after 2 minutes of shaking on an orbital shaker and quantified using the TECAN Infinity M200Pro instrument.

[0290] 6. Study of the antiviral efficacy of aReps in vivo on the hamster model Virus

[0291] The SARS-CoV-2 isolate (BetaCoV / IdF0372 / 2020) was provided by Prof. Manuguerra (Institut Pasteur). After two amplification passages on the VeroEô line (ATCC), the seed stock was titrated in VeroEô cells at a concentration of 6.0 log10 TCID50 / ml. The seed stock was thawed and diluted in cold phosphate-buffered saline (PBS) before infection. Infection and treatment of hamsters

[0292] Animals

[0293] The experiments were carried out on 16 10-week-old male Syrian golden hamsters (Mesocricetus auratus) supplied by Janvier Labs. The animals were housed alone per cage in a BSL-III safety level animal facility.

[0294] The animals were raised according to INRAE ​​guidelines in compliance with Resolution No. 493 on the protection of animal welfare within the European Union. The animals were checked daily for obvious signs of disease.

[0295] Study design

[0296] Two groups of eight hamsters were instilled intranasally with 0.8 mg of composite aRep F9-C2 or 0.8 mg of aRep H7 (control aReps recognizing an influenza virus protein. SEQ ID NO. 63) in a volume of 80 pL of PBS.

[0297] After 1 h, the animals were infected intranasally with 5.103 TCID50 of SARS-CoV-2 (diluted in 80pL of DMEM). The animals were weighed daily and daily nasal swabs were used to measure the rate of viral particle production during infection. Subsequently, the animals were euthanized after 1 or 3 days post infection (D1 / D3, i.e. 4 hamsters per group). On each animal, the olfactory mucosa (major site of virus replication in the respiratory sphere) and part of the lungs were taken for molecular analyses. Virological tests

[0298] Daily nasal swabs were performed according to the protocol described in Montrache-Leroy et al., 2021. J Gen Virol. Mar;102(3).

[0299] Once the animals were euthanized on D1 or D3, part of the lungs and the olfactory epithelium were ground in trizol to extract the mRNA and the quantity of virus was measured by RT-qPCR focusing on the gene coding for the E protein (SARS-CoV-2 envelope protein) and normalizing on the expression of actin. Sense primer (5' -> 3') Antisense primer (5' -> 3') Protein E ACAGGTACGTTAATAGTTAAT AGCGT (SEQ ID NO. 58) ATATTGCAGCAGTACGCA CACA (SEQ ID NO. 59) Actin ACTGCCGCATCCTCTTCCT (SEQ ID NO. 60) TCGTTGCAATGGTGATGAC (SEQIDNO. 61) Example 2: Results 1. The alphaReps

[0300] Twenty-two positive clones (Bl, B4, B12, Cl, C2, C4, C7, C12, D3, D7, D10, E6, E12, F2, F7, F9, Gl, G3, G5, H6, H10 and H12) were selected as being specific for the RBD domain. Sequencing of the clones revealed aReps of different sizes, consisting mainly of 3 to 8 repeats of the 31 amino acid motif. The eight clones C2, C7, C12, D7, F7, F9, Gl, H10 and H12 were identified as having the strongest signal in the ELISA test and were retained for further characterization.

[0301] Measurement of aReps affinity for the RBD of SARS-Co V-2

[0302] A first test was carried out by measuring the rate of fixation and dissociation of aReps concentrated at 1 pM on the RBD domain ([Fig.l]). At this concentration, aReps C2, C12, F9, Gl, H10 and H12 have low dissociation rates unlike C7, D7 and F7.

[0303] The dissociation constant (KD) was calculated for the aReps C2 and F9 on the RBD domain and SI subunit (Fig. 2A-2B-2C-2D). They are 0.29 nM for C2 and F9 (Figs 2A and 2C) on RBD and 0.31 nM for C2 (Fig. 2B) and 1.16 nM for F9 (Fig. 2D) on SI domain, which makes them monovalent ligands of interest.

[0304] The avidity of the composite aRep F9-C2 is 0.091 nM, providing increased efficacy compared to F9 or C2 alone ([Fig.2E]).

[0305] Neutralizing power of aReps on pseudotyped particles of SARS- CoV-2 and the virus itself

[0306] First, the neutralizing power of aReps was measured by pre-incubating dilutions of aRep with pseudo-typed particles expressing the SARS-CoV-2 S protein before depositing the mixture on target cells, as previously described. The ability of virions to infect target cells is measured by the expression of a reporter gene, that of firefly luciferase, present in the virions. The pseudo-typed particles contain a reporter gene (firefly luciferase) which makes it possible to quantify the ability of alphaReps to block infection. The infection is previously calibrated in the absence of alphaRep to obtain a signal / background ratio greater than 1000. Fig. 3A shows that aReps C2, C7, F9 and H12 neutralize the pseudo-typed lentivirus of the S protein with an efficiency dependent on their concentrations.The aRep Gl, which was selected to bind to the RBD, and the aRep H7, which does not recognize the S protein, do not neutralize the protein. These results suggest that the aRep Gl is not able to block the S-ACE2 interaction by binding to a domain distant from the ACE2-interacting domain. Neither aRep neutralizes a pseudotype carrying the vesicular stomatitis virus G protein (VSVG).

[0307] In a second step, dilutions of aReps were co-incubated with SARS-CoV-2 before depositing on susceptible cells (Fig. 3B). The survival of cells to infection is quantified by measuring the amount of intracellular ATP in the infected wells. The four aReps C2, C7, F9 and H12 protect from infection depending on their concentrations, with aRep C2 having the strongest neutralizing power with an IC50 of 0.27 pM. aRep H7 does not neutralize the virus.

[0308] Rationale for increasing the binding specificity of neutralizing aReps

[0309] Two strategies have prevailed in the generation of covalent or non-covalent assemblies of aRep in order to increase their avidity for the S protein, and therefore their neutralizing power. The first consisted of constructing dimers covalently associating the C2 and F9 aReps, namely the C2-F9 (SEQ ID NO. 13) and F9-C2 (SEQ ID NO. 12) constructs in which the two aReps are separated by a 25 amino acid spacer domain consisting of serines and glycines (SEQ ID NO. 19). A second strategy consisted of multimerizing a sequence allowing trimerization, called here Foldon (SEQ ID NO. 54), at the C-terminal end of the aReps. The aRep-foldon protein trimerizes non-covalently. The F9-C2 and C2-foldon composite constructs (SEQ ID NO. 14) were efficiently expressed. The F9-C2 and C2-foldon composite constructs are highly soluble in water. This allows, among other things, a higher production yield.

[0310] Neutralizing power of the aRep composite F9-C2 construction

[0311] The neutralizing power of the F9-C2 composite aRep was quantified as previously by mixing dilutions of the F9-C2 composite aRep with fixed amounts of particles pseudo-typed with the S protein or SARS-CoV-2 virus (Fig. 4A-AB). Similarly, the pseudo-typed particles contain a reporter gene (firefly luciferase) that allows quantification of the inhibitory power of alphaReps. The infection is pre-calibrated to obtain a signal-to-background ratio greater than 1000. The F9-C2 construct very effectively neutralizes particles pseudo-typed with the S protein as well as the SARS-CoV-2 virus and more effectively than C2 alone as well as F9 and C2 together (F9+C2). The IC50 of F9-C2 on SARS-CoV-2 is 8 nM while those of C2 and F9 are around 250 nM (Table 1).

[0312] [Tables 1] <3 REP 0.27 C2 -F9 0 28 F9-C2 0.008

[0313] Neutralizing power of the composite constructs aRep C2-C2-C2, C2-foldon and F9-foldon.

[0314] Fusions of the reading frames of the F9 aRep, three C2 aReps (SEQ ID NO. 11) or with the Foldon peptide (C2-foldon) increase their neutralizing activity. [Fig. 5] shows that the C2-foldon neutralizes SARS-CoV-2 more effectively than C2 alone, and that its neutralizing activity is of the same order of magnitude, or even higher, than that of the F9-C2 composite aRep. The C2-C2-C2 composite aRep also has a higher neutralizing activity than C2 alone (not shown). These couplings increase the avidity for the S protein of SARS-CoV-2.

[0315] Neutralizing activity of composite aRep F9-C2 on SARS-CoV-2 variants

[0316] Pseudo-typed MLVs carrying the specific mutations in the RBD domain of the alpha, beta, gamma and delta / kappa variants were produced to carry out infections of HEK-293T-ACE2 cells. The S proteins produced carry the N501Y mutation (representative of the alpha variant), the mutations K417N, E484K, N501Y (representative of the beta variant), K417T, E484K, N501Y (representative of the gamma variant) and L452R, E484Q (representative of the delta / kappa variants). Figs 6a-6b and Figs 6c-6d-6e show that the neutralizing power of F9-C2 is not or only slightly affected on the mutants representative of the alpha and beta variants if they are compared to the Wuhan-Hu-1 type strain. The neutralizing power of F9-C2 is moderately affected on the Representative mutant of the gamma variant. The representative mutant of the delta and kappa variants is less well neutralized by F9-C2 than its counterparts. All four variants analyzed are more sensitive to F9-C2 neutralization than F9 and C2 alone, highlighting the cooperative effect associated with the multimerization of F9 and C2.

[0317] Antiviral activity of composite aRepF9-C2 in vivo in a hamster model

[0318] The antiviral activity of the composite aRep F9-C2 was measured on the Syrian golden hamster model, which reflects the non-severe syndromes of human infections in terms of cell tropism, weight loss, and kinetics of SARS-CoV-2 presence. Nasal inoculation of the composite aRep F9-C2 1 h before SARS-CoV-2 infection limits the presence of the virus in the olfactory mucosa by a factor of 30 on D1 and by a factor of 2.3 on D3 post-infection compared to nasal inoculation of an aRep (H7) unrelated to SARS-CoV-2 (Fig. 7A). In the lungs, it is limited by a factor of 5 and 2.5 on D1 and D3, respectively.

[0319] The antiviral efficacy of aReps was also evaluated by measuring the production of infectious viral particles produced in the nasal cavity of infected animals. It is reduced by a factor of 50 at D2 at the peak of production (Fig. 7B).

[0320] In conclusion, the aReps of the present disclosure exhibit highly specific activity for the SARS-CoV-2 S protein and enable strong neutralization of the SARS-CoV-2 virus in vitro and in vivo.

[0321] Among these identified aReps, C2, F9 and H12 have strong neutralizing and protective activity, more particularly C2. Homologous (C2-C2-C2 or C2-foldon) or heterologous (F9-C2) multimerization of aReps allows for increased neutralizing activity. The composite aRep F9-C2 has protective activity in a hamster infection model.

[0322] Thus, a polypeptide of formula (I) or a composite polypeptide according to the present description is capable of treating and / or preventing a condition caused by a SARS-CoV-2 infection. Reference to sequences SEQ ID NO.l - aRep C2:

[0323] MRGSHHHHHH

[0324] TDPEKVEMYIKNLQDDSVKVRFFAAYALGKI

[0325] GDERAVEPLIKALKDEDANVRISAAAALGKI

[0326] INTRODUCTION TO GDERAVEPLICALKDEDA

[0327] GDERAVEPLIKDEDENVRREAARALGQI

[0328] GGERVRAAMEKLAETGTGFQVAVAN LIST SEQ ID NO. 2 - aRep C7 :

[0329] MRGSHHHHHH

[0330] TDPECQDSCRIPTION

[0331] GDERAVEPLIKDEDTDVRQTAATALGQI

[0332] GDERAVE APPLICATION ANALYSIS

[0333] GDERAVEPLICALKDEDENVRYSAASALGKI

[0334] GGERVRAAAMEKLAETGTGFQVAVANOLATION LIST SEQ ID NO. 3 - aRep C12 :

[0335] MRGSHHHHHH

[0336] TDPEKVEMYIKNLQDDSGTIEDRI

[0337] INTRODUCTION TO GDERAVEPLICAL

[0338] GDERAVEPLICALKDEDSWORK PROBLEM

[0339] GDERAVEPLICALKDESDVRTSAOPTION

[0340] GGERVRAAMEKLAETGTGFQVAVANOLATION LIST SEQ ID NO. 4 - aRep D7 :

[0341] MRGSHHHHHH

[0342] TDPECQUEMYIKNLQDDSGLVRIIAASALGKI

[0343] GDERAVEPLIKDEDTNVRVAAAGALGQI

[0344] GDERAVEPLIKALKDEDPSVRQSAASALGKI

[0345] GDERAVEPLIKALKDEDVNVRQAAASALGKI

[0346] GGERVRAAMEKLAETGTGFARKVAVNYLETHKSLIS SEQ ID NO. 5 - aRep E12 :

[0347] MRGSHHHHHH

[0348] TDPEKVEMYIKNLQDDSSNVRFSAAFALGKI

[0349] GDERAVEPLIKALKDEDVNVRLRAALALGKI

[0350] GDERAVEPLIKALKDEDSDVRVAAAVALGKI

[0351] GDERAVEPLIKALKDEDAQVRLSAADALGKI

[0352] GDERAVEPLIKALKDEDGAVRASAAYALGEI

[0353] GDERAVEPLIKALKDEDGYVRARAAFALGKI

[0354] GDERAVEPLIKALKDEDSDVRLTAAKALGQI

[0355] GDERAVEPLIKALKDEDLGVRYGAATALGEI

[0356] GGERVRAAMEKLAETGTGFARKVAVNYLETHKSLIS

[0357] SEQ ID NO. 6 aRep F7 :

[0358] MRGSHHHHHH

[0359] TDPEKVEMYIKNLQDDSLIVRDDAADALGKI

[0360] GDERAVEPLIKALKDEDGEVRLSAARALGEI

[0361] GDERAVEPLIKALKDEDGA VRRLAADALGKI

[0362] GDERAVEPLIKALKDEDAAVRLRAALALGQI

[0363] GDERAVEPLIKALKDEDKNVRRVAAEALGQI

[0364] GGERVRAAMEKLAETGTGFARKVAVNYLETHKSLIS SEQ ID NO. 7 - aRep F9 :

[0365] MRGSHHHHHH

[0366] TDPEKVEMYIKNLQDDSVLVRYNAAFALGKI

[0367] GDERAVEPLIKALKDEDRYVRFSAALALGEI

[0368] GDERAVEPLIKALKDEDGYVRASAAWALGQI

[0369] GDERAVEPLIKALKDEDWRVRLSAAKALGKI

[0370] GDERAVEPLIKALKDEDGEVRVRAANALGKI

[0371] GDERA VEPLIKALKDEDGYVRRA AAGALGQI

[0372] GDERA VEPLIKALKDEDWLVRQSAATALGKI

[0373] GDERA VEPLIKALKDEDPSVRFSAAAALGEI

[0374] GDERA VEPLIKALKDEDGFVRLSAASALGQI

[0375] GGERVRAAMEKLAETGTGFARKVAVNYLETHKSLIS SEQ ID NO. 8 - aRep G1 :

[0376] MRGSHHHHHH

[0377] TDPEKVEMYIKNLQDDSGTIEDRI

[0378] GDERA VEPLIKALKDEDGAVRQSAASALGQI

[0379] GDERA VEPLIKALKDEDGYVRQRAADALGKI

[0380] GGERVRAAMEKLAETGTGFARKVAVNYLETHGSLIS SEQ ID NO. 9 - aRep H10 :

[0381] MRGSHHHHHH

[0382] TDPEKVEMYIKNLQDDSMLVRSYAANALGKI

[0383] GDERA VEPLIKALKDEDLAVRRAAATALGKI

[0384] GDERA VEPLIKALKDEDSAVRQSAARALGQI

[0385] GDERA VEPLIKALKDEDPWVRRAAAYALGQI

[0386] GDERA VEPLIKALKDEDPWVRKTAAEALGKI

[0387] GDERA VEPLIKALKDEDTNVRYRAAQALGKI

[0388] GDERA VEPLIKALKDEDAEVRRVAAVALGEI

[0389] GDERA VEPLIKALKDEDSDVRYGAAVALGQI

[0390] GGERVRAAMEKLAETGTGFARKVAVNYLETHKSLIS SEQ ID NO. 10 - aRep H12 :

[0391] MRGSHHHHHH

[0392] TDPEKVEMYIKNLQDDSGHVRVFAAYALGKI

[0393] GDERA VEPLIKALKDEDSDVRISAANALGKI

[0394] GDERA VEPLIKALKDEDSAVRQSAAEALGKI

[0395] GDERA VEPLIKALKDEDSNVRRNAARALGQI

[0396] GDERA VEPLIKALKDEDAAVRKAAALALGKI

[0397] GDERAVEPLIKALKDEDSYVRQSAAEALGKI

[0398] GGERVRAAMEKLAETGTGFARKVAVNYLETHKSLIS SEQ ID NO : 11 - aRep C2-C2-C2 :

[0399] MRGSHHHHHH

[0400] TDPEKVEMYIKNLQDDSVKVRFFAAYGKI [0401 ] GDERA VEPICALKDED AND FROZEN AAAALGKI

[0402] INTRODUCTION TO GDERA VEPLICALC

[0403] GDERA VEPLICALCDEDENVRREAARGQQY

[0404] GGERVRAAMEKLAETGTGFQVAVANOLATION LIST

[0405] GGGGSGGGGGGGGGGGSGGGGS

[0406] TDPEKVEMYIKNLQDDSVKVRFFAAYALGKI

[0407] GDERA VEPLICALDED FREEZING ALGKI

[0408] INTRODUCTION TO GDERA VEPLICALC

[0409] GDERA VEPLICALKDEDENVRREAARGQQY

[0410] GGERVRAAMEKLAETGTGFQVAVANOLATION LIST

[0411] GGGGSGGGGGGGGGGGSGGGGS

[0412] TDPEKVEMYIKNLQDDSVKVRFFAAYALGKI

[0413] GDERA VEPLICALKDED FREEZING ALGKI

[0414] INTRODUCTION TO GDERA VEPLICALC

[0415] GDERA VEPLICALCDEDENVRREAARGQQY

[0416] GERVRAAAMEKLAETGTGKVA VOLUME LIST SEQ ID NO. 12 - aRep F9-C2:

[0417] MRGSHHHHHH

[0418] TDPEKVEMYIKNLQDDS VLVRYNAAFALGKI

[0419] GDERA VEPLIKALKDEDRYVRFSAALALGEI

[0420] GDERA VEPLIKALKDEDGYVRASAAWALGQI [0421 ] GDERA VEPLIKALKDEDWRVRLS A AKALGKI

[0422] GDERA VEPLIKALKDEDGEVRVRAANALGKI

[0423] GDERA VEPLIKALKDEDGYVRRAAAAGALGQI

[0424] WHERE IS THE NAME OF THE VEPLIKALKDEDWLVRQSAATALGKI?

[0425] GDERA VEPLIKALKDEDPSVRFSAAAALGEI

[0426] GDERA VEPLIKALKDEDGFVRLSAASALGQI

[0427] GGERVRAAMEKLAETGTGFARKVA VNYLETHKSLIS

[0428] GGGGSGGGGSGGGGSGGGGSGGGGS

[0429] TDPEKVEMYIKNLQDDSVKVRFFAAYALGKI

[0430] GDERA VEPLIKALKDEDANVRISAAAALGKI

[0431] GDERA VEPLIKALKDEDAAVRQSAASALGQI

[0432] GDERA VEPLIKALKDEDENVRREAARALGQI

[0433] GGERVRAAMEKLAETGTGFARKVAVNYLETHKSLIS SEQ ID NO. 13 - aRep C2-F9:

[0434] MRGSHHHHHH

[0435] TDPEKVEMYIKNLQDDSVKVRFFAAYALGKI

[0436] GDERA VEGETABLE LIQUID FREEZING ALGKI

[0437] INTRODUCTION TO GDERA VEPLICALC

[0438] GDERA VEPLICALKDEDENVRREAARGQQY

[0439] GGERVRAAMEKLAETGTGFQVAVAN LIST

[0440] GGGGSGGGGGGGGGGGSGGGGS [0441 ] TDPEKVEM YIKNLQDDS VLVR YNAAFALGKI

[0442] GDERA VEPLICALCDEDRYVRFSAALALGEI

[0443] INTRODUCTION TO GDERA VEPLICALKDEDGYVRAS

[0444] GDERA VEPLIKKDEDWRVRLSAKAKKI

[0445] GDERA VEHICLE REDUCTION ANALYSIS

[0446] GDERA VEPLICALCDEDGYVRRAAAAGQII

[0447] GDERA VEPLIKKDEDWLVRQSAATALGKI

[0448] GDERA VEPLIKKDEDPSVRFSAAAALGEI

[0449] INTRODUCTION TO GDERA VEPLICALCDEDGFVR

[0450] GGERVRAAAMEKLAETGTGFQVAVAN LIST SEQ ID NO. 14 - aRep C2-foldon : [0451 ] MRGSHHHHHH

[0452] TDPEKVEM YIKNLQDDS VKVRFFAAYALGKI

[0453] GDERA VEPLIKALKDEDANVRISAAAALGKI

[0454] GDERA VEPLIKALKDEDAAVRQSAASALGQI

[0455] GDERA VEPLIKALKDEDENVRREAARALGQI

[0456] GGERVRAAMEKLAETGTGFARKVAVNYLETHKSLIS

[0457] GSAGSAGGSGGAGGSGYIPEAPRDGQAYVRKDGEWVLLSTFL SEQ ID NO. 15 - aRep F9-foldon :

[0458] MRGSHHHHHH

[0459] TDPEKVEMYIKNLQDDSVLVR YNAAFALGKI

[0460] GDERA VEPLIKALKDEDRYVRFSAALALGEI [0461 ] GDERA VEPLIKALKDEDGYVRASAAWALGQI

[0462] GDERA VEPLIKALKDEDWRVRLSAAKALGKI

[0463] GDERA VEPLIKALKDEDGEVRVRAANALGKI

[0464] GDERA VEPLIKALKDEDGYVRRAAAGALGQI

[0465] GDERAVEPLIKALKDEDWLVRQSAATALGKI

[0466] GDERAVEPLIKALKDEDPSVRFSAAAALGEI

[0467] GDERAVEPLIKALKDEDGFVRLSAASALGQI

[0468] GGERVRAAMEKLAETGTGFARKVAVNYLETHKSLIS

[0469] GSAGSAGGSGGAGGSGYIPEAPRDGQAYVRKDGEWVLLSTFL

[0470] SEQ ID NO. 16 : GDERAVEPLIKALKDED

[0471] SEQ ID NO. 17:MRGSHHHHHH

[0472] SEQ ID NO. 18 (ct): GGERVRAAMEKLAETGTGFARKVAVNYLETHXSLIS

[0473] X étant K ou G

[0474] SEQ ID NO. 19 - peptide de liaison: GGGGGSGGGGSGGGGSGGGGSGGGGS

[0475] SEQ ID NO. 20 (Nt de C2):

[0476] MRGSHHHHHHTDPEKVEMYIKNLQDDSVKVRFFAAYALGKI

[0477] SEQ ID NO. 21 (Nt de C7):

[0478] MRGSHHHHHHTDPEKVEMYIKNLQDDSKIVRFFAAVALGKI

[0479] SEQ ID NO. 22 (Nt de C12): MRGSHHHHHHTDPEKVEMYIKNLQDDSGTIEDRI

[0480] SEQ ID NO. 23 (Nt de D7): [0481 ] MRGSHHHHHHTDPEKVEMYIKNLQDDSGLVRIIAASALGKI

[0482] SEQ ID NO. 24 (Nt de E12):

[0483] MRGSHHHHHHTDPEKVEMYIKNLQDDSSNVRFSAAFALGKI

[0484] SEQ ID NO. 25 (Nt de F7):

[0485] MRGSHHHHHHTDPEKVEMYIKNLQDDSLIVRDDAADALGKI

[0486] SEQ ID NO. 26 (Nt de F9):

[0487] MRGSHHHHHHTDPEKVEMYIKNLQDDSVLVRYNAAFALGKI

[0488] SEQ ID NO. 27 (Nt de Gl): MRGSHHHHHHTDPEKVEMYIKNLQDDSGTIEDRI

[0489] SEQ ID NO. 28 (Nt de H10):

[0490] MRGSHHHHHHTDPEKVEMYIKNLQDDSMLVRSYAANALGKI

[0491] SEQ ID NO. 29 (Nt de H12):

[0492] MRGSHHHHHHTDPEKVEMYIKNLQDDSGHVRVFAAYALGKI

[0493] SEQ ID NO. 30: aRep B1:

[0494] MRGSHHHHHH

[0495] TDPEKVEMYIKNLQDDSMGVRASAAFALGKI

[0496] GDERAVEPLIKALKDEDWLVRQTAARALGQI

[0497] GDERAVEPLIKALKDEDSDVRLSAAAALGEI

[0498] GDERAVEPLIKALKDEDPDVRFSAAQALGEI

[0499] GDERAVEPLIKALKDEDPWVRSSAASALGEI

[0500] GGERVRAAMEKLAETGTGFARKVAVNYLETHKSLIS

[0501] SEQ ID NO. 31: aRep B4:

[0502] MRGSHHHHHH

[0503] TDPEKVEMYIKNLQDDSTQVRIDAAAALGKI

[0504] GDERAVEPLIKALKDEDPAVRQSAAYALGQI

[0505] GDERA VEPLIKALKDEDSNVRIEAARALGQI

[0506] GGERVRAAMEKLAETGTGFARKVAVNYLETHKSLIS

[0507] SEQ ID NO. 32 : aRep B12 :

[0508] MRGSHHHHHH

[0509] TDPEKVEMYIKNLQDDSLLVRVIAAYALGKI

[0510] GDERA VEPLIKALKDEDPVRIRAAFALGQI

[0511] GDERA VEPLIKALKDEDSA VRQS AAE ALGEI

[0512] GDERA VEPLIKALKDEDGAVRETAASALGKI

[0513] GGERVRAAMEKLAETGTGFARKVA VNYLETHKSLIS

[0514] SEQ ID NO. 33 : aRep Cl :

[0515] MRGSHHHHHH

[0516] TDPEKVEMYIKNLQDDSQTVRIVAANALGKI

[0517] GDERA VEPLIKALKDEDPAVRQSAAGALGKI

[0518] GDERA VEPLIKALKDEDKNVRLNAATALGQI

[0519] GDERA VEPLIKALKDEDGYVRIRAARALGEI

[0520] GDERA VEPLIKALKDEDGYVRTAAAYALGKI

[0521] GDERA VEPLIKALKDEDRAVREAAAAEALGKI

[0522] GGERVRAAMEKLAETGTGFARKVA VNYLETHKSLIS

[0523] SEQ ID NO. 34 : aRep C4 :

[0524] MRGSHHHHHH

[0525] TDPEKVEMYIKNLQDDSVPVRDNAAVALGKI

[0526] GDERA VEPLIKALKDEDSRVRQRAAKALGKI

[0527] GGERVRAAMEKLAETGTGFARKVA VNYLETHKSLIS SEQ ID NO. 35 : aRep D3 :

[0528] MRGSHHHHHH

[0529] TDPEKVEMYIKNLQDDSGLVRIIAASALGKI

[0530] GDERA VEPLIKALKDEDTNVRVAAAGALGQI

[0531] GDERA VEPLIKALKDEDPSVRQSAASALGKI

[0532] GDERA VEPLIKALKDEDVNVRQAAASALGKI

[0533] GGERVRAAMEKLAETGTGFARKVA VNYLETHKSLIS

[0534] SEQ ID NO. 36 : aRep D10 :

[0535] MRGSHHHHHH

[0536] TDPEKVEMYIKNLQDDSNSVRSSAADALGKI

[0537] GDERA VEPLIKALKDEDPWVRETAAFALGQI

[0538] GDERAVEPLIKALKDEDRYVRISAAFALGKI

[0539] GDERAVKPLIKALKDEDYSVRQSAAEALGEI

[0540] GDERAVEPLIKALKDEDAEVRIAAARALGEI

[0541] GDERAVEPLIKALKDEDGYVRLSAAKALGKI

[0542] GDERAVEPLIKALKDEDWRVRFSAAEALGKI

[0543] GDERAVEPLIKALKDEDYEVRRAAATALGQI

[0544] GDERAVEPLIKALKDEDVNVRYSAAIALGKI

[0545] GGERVRAAMEKLAETGTGFARKVAVNYLETHKSLIS

[0546] SEQ ID NO. 37 : aRep E6 :

[0547] MRGSHHHHHH

[0548] TDPEKVEMYIKNLQDDSLLVRTYAAAALGKI

[0549] GDERAVEPLIKDEDPDVRIAAANALGQI

[0550] GDERAVEPLIKDEDPAVRQSAAAALGKI

[0551] GDERAVEPLIKDEDVNVRLAAAEALGKI

[0552] GGERVRAAMEKLAETGTGFQVAVAN OLYTHKLIST

[0553] SEQ ID NO. 38 : aRep F2 :

[0554] MRGSHHHHHH

[0555] TDPEKVEMIKNLQDDSKQVRYVAADALGKI

[0556] GDERAVEPLICALKDEDTDVRLTARALGKI

[0557] GDEHAVEPLIKDEDAAVRQSAAAALGKI

[0558] GDERAVEPLIKDEDKNVRSEAAQALGEI

[0559] GGERVRAAMEKLAETGTGFQVAVANYL LIST SEQ ID NO. 39 : aRep G3 :

[0560] MRGSHHHHHH

[0561] TDPEKVEMYIKNLQDDSGTIEDRI

[0562] GDERAVE APPLICATION DESCRIPTION OPTION

[0563] GDERAVEPLIKDEDGFVRQRAAAALGKI

[0564] GERERVRAAMEKLAETGTGFQVAVAN LIST SEQ ID NO. 40 : aRep G5 :

[0565] MRGSHHHHHH

[0566] TDPEKVEMYIKNLQDDSAHVRNVAATALGKI

[0567] GDERAVEPLIKALKDEDWLVRWSAAVALGKI

[0568] GDERAVEPLIKALKDEDTDVRSRAALALGKI

[0569] GDERAVEPLIKALKDEDVFVRWRAAEALGKI

[0570] GDERAVEPLIKALKDEDRYVRYAAALALGKI

[0571] GDERAVEPLIKALKDEDGYVRIAAASALGKI

[0572] GDERAVEPLIKALKDEDPTVRFSAARALGEI

[0573] GDERAVEPLIKALKDEDAEVRREAAEALGKI

[0574] GDERAVEPLIKALKDEDPWVRYAAAEALGEI

[0575] GGERVRAAMEKLAETGTGFARKVAVNYLETHKSLIS

[0576] SEQ ID NO. 41 : aRep H6 :

[0577] MRGSHHHHHH

[0578] TDPEKVEMYIKNLQDDSQMVRFIAASALGKI

[0579] GDERAVEPLIKALKDEDARVRQSAARALGKI

[0580] GDERA VEPLIKALKDED VEVRMS AARALGQI

[0581] GDERA VEPLIKALKDEDA A VRQS AALALGKI

[0582] GDERA VEPLIKALKDEDENVRQEAAKALGKI

[0583] GGERVRAAMEKLAETGTGFARKVA VNYLETHKSLIS

[0584] SEQ ID NO. 42 (Nt de B1) :

[0585] MRGSHHHHHHTDPEKVEMYIKNLQDDSMGVRASAAFALGKI

[0586] SEQ ID NO. 43 (Nt de B4):

[0587] MRGSHHHHHHTDPEKVEMYIKNLQDDSTQVRIDAAAALGKI

[0588] SEQ ID NO. 44 (Nt de B12):

[0589] MRGSHHHHHHTDPEKVEMYIKNLQDDSLLVRVI AA YALGKI

[0590] SEQ ID NO. 45 (Nt de C1):

[0591] MRGSHHHHHHTDPEKVEMYIKNLQDDSQTVRIVAANALGKI

[0592] SEQ ID NO. 46 (Nt de C4):

[0593] MRGSHHHHHHTDPEKVEMYIKNLQDDSVPVRDNAAVALGKI

[0594] SEQ ID NO. 47 (Nt de D3):

[0595] MRGSHHHHHHTDPEKVEMYIKNLQDDSGLVRIIAASALGKI

[0596] SEQ ID NO. 48 (NT de D10):

[0597] MRGSHHHHHHTDPEKVEMYIKNLQDDSNSVRSSAADALGKI

[0598] SEQ ID NO. 49 (Nt de E6):

[0599] MRGSHHHHHHTDPEKVEMYIKNLQDDSLLVRTYAAAALGKI

[0600] SEQ ID NO. 50 (Nt de F2): [0601 ] MRGSHHHHHHTDPEKVEMYIKNLQDDSKQ VRYVAADALGKI

[0602] SEQ ID NO. 51 (Nt de G3): MRGSHHHHHHTDPEKVEMYIKNLQDDSGTIEDRI

[0603] SEQ ID NO. 52 (Nt de G5):

[0604] MRGSHHHHHHTDPEKVEMYIKNLQDDSAHVRNVAATALGKI

[0605] SEQ ID NO. 53 (Nt de H6):

[0606] MRGSHHHHHHTDPEKVEMYIKNLQDDSQMVRFIAASALGKI

[0607] SEQ ID NO. 54 (foldon): GSAGSAGGSGGAGGSGYIPEAPRDGQAYVRKDGEWVLLSTFL

[0608] SEQ ID NO. 55: segment of ADN code for “peptide signal-RBD-His tag” ctcgagATGGGCATCCTGCCCAGCCCCGGAATGCCCGCTCTGCTGTCCCTGGTGTCCCTGCT

[0609] SEQ ID NO. 56: (Domain RBD)

[0610] RVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKC5

[0611] SEQ ID NO. 57: Peptide signal-RBD-His tag

[0612] MGILPSPGMPALLSLVSLLSVLLMGCVAETGTRVQPTESIVRFPNITNLCPFGEVFNATRFA

[0613] SEQ ID NO. 58 (Amor sens Protein E): ACAGGTACGTTAATAGTTAATAGCGT

[0614] SEQ ID NO. 59 (Amorce antisense Protein E): ATATTGCAGCAGTACGCACACA

[0615] SEQ ID NO. 60: ACTGCCGCATCCTCCTTCCT

[0616] SEQ ID NO. 61: TCGTTGCCAATGGTGATGAC

[0617] SEQ ID NO. 62: X x

[0618] Start to the next: 1 year after A, E, T, S, P, V, G, L, K, R, W or Y; 2nd X étant N, A, D, T, R, S, Q, Y, G, E, L, F, W or N; 3e X étant I, Q, R, Y, K, T, V, L, A, F, E, S, M or W; 4e X étant S, E, T, A, R, G, L, V or N; 5e 6e X étant K, Q or E SEQ ID NO. 63 : alpha Rep H7

[0619] MRGSHHHHHH

[0620] TDPEKVEMYIKNLQDDSNAVRYSAATALGKI

[0621] RDERA VEPLIKALKDEDGYVRYA AAEALGKI

[0622] GDERAVEPLIKALKDEDGYVRRAAAQALGKI

[0623] GDERAVEPLIKALKDEDENVRWSAALALGKI

[0624] GDERAVEPLIKALKDEDYAVRRNAAKALGKI

[0625] GDERAVEPLIKALKDEDRFVRTAAAKALGKI

[0626] GDERAVEPLIKALKDEDTLVREDAARALGKI

[0627] GDERAVEPLIKALKDEDTDVRRAAARALGKI

[0628] GDERAVEPLIKALKDEDWLVRLSAARALGKI

[0629] GGERVRAAMEKLAETGTGFARKVAVNYLETHKSLIS

[0630] SEQ ID NO. 64 : Gène du domaine RBD du SARS-CoV-2

[0631] AGAGTGCAGCCCACCGAGTCC ATCGTGCGCTTTCCCAAC ATCACAAACCTGTGCCCCT List of documents cited

[0632] Barnes, C. et al. (2020) SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies. Nature 588, 682-687.

[0633] Baum, A. et al. (2020) REGN-COV2 antibodies prevent and treat SARS-CoV-2 infection in rhésus macaques and hamsters. Science 370, 1110-1115

[0634] Cao, L. et al. (2020) De novo design of picomolar SARS-CoV-2 miniprotein inhibitors. Science 370:426–431.

[0635] Chen, P. (2020) SARS-CoV-2 neutralizing antibody LYCoV555 in outpatients with Covid-19. N. Engl. J. Med. Published online October 28, 2020.

[0636] Custodio, T.F. (2020) Sélection, biophysical and structural analysis of synthetic nanobodies that effectively neutralize SARS-CoV-2. Nat Commun. 11:5588.

[0637] Czajka, T.F. (2021) Slaying SARS-CoV-2 One (Single-domain) Antibody at a Time. Trends in Microbiology 29, 195-203

[0638] Dhama K, Khan S, Tiwari R, et al. Coronavirus Disease 2019-COVID-19. Clin Microbiol Rev. 2020;33(4):e00028-20. Published 2020 Jun 24. doi:10.1128 / CMR.00028-20

[0639] Fagre, A.C. (2020) A Potent SARS-CoV-2 Neutralizing Human Monoclonal Antibody That Reduces Viral Burden and Disease Severity in Syrian Hamsters. Front Immunol 11:614256

[0640] Güttler, T. et al. (2021) Neutralization of SARS-CoV-2 by highly potent, hyperthermostable, and mutation-tolérant nanobodies. EMBO J. el07985.

[0641] Hanke, L. et al. (2020) An alpaca nanobody neutralizes SARS-CoV-2 by blocking receptor interaction. Nat. Commun. 11, 4420

[0642] Hansen, J. et al. (2020) Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail. Science 369, 1010-1014

[0643] Huo, J. et al. (2020) Neutralizing nanobodies bind SARS-CoV-2 spike RBD and block interaction with ACE2. Nat. Struct. Mol. Biol. 27, 846-854

[0644] Ma, H. et al. (2021) Potent Neutralization of SARS-CoV-2 by Hetero-Bivalent Alpaca Nanobodies Targeting the Spike Receptor-Binding Domain. J Virol. 95:e02438-20.

[0645] Millet et Whittaker, 2016 Murine Leukemia Virus (MLV)-based Coronavirus Spike-pseudotyped Particle Production and Infection. Bio Protoc. 6:e2035

[0646] Montrache-Leroy et al., 2021 Hamster and ferret experimental infection with intranasal low dose of a single strain of SARS-CoV-2. J Gen Virol. Mar; 102(3)

[0647] Li, W. et al. (2020) Rapid identification of a human antibody with high prophylactic and therapeutic efficacy in three animal models of SARS-CoV-2 infection. Proc. Natl. Acad. Sci. U. S. A. 117, 29832-29838

[0648] Li, W. et al. (2020) High potency of a bivalent human V(H) domain in SARS-CoV-2 animal models. Cell 183, 429-441.e416

[0649] Raybould, M.I.J. et al. (2020) CoV-AbDab: the coronavirus antibody database. Bioinformatics, btaa739

[0650] Schoof, M. et al. (2020) An ultrapotent synthetic nanobody neutralizes SARS-CoV-2 by stabilizing inactive Spike. Science 370, 1473-1479

[0651] Sun X, Belouzard S, Whittaker GR. Molecular architecture ofthe bipartite fusion loops of vesicular stomatitis virus glycoprotein G, a class III viral fusion protein. J Biol Chem. 2008 Mar 7; 283(10):6418-27

[0652] Walser, M. et al. (2020) Highly potent anti-S ARS-CoV-2 multivalent DARPin therapeutic candidates, https: / / www.biorxiv.org / content / 10.! 101 / 2020.08.25.256339v3

[0653] Wrapp, D. et al. (2020) Structural basis for potent neutralization of betacoronaviruses by single-domain camelid antibodies. Cell 181, 1004-1015.el015

[0654] Xiang, Y. et al. (2020) Versatile and multivalent nanobodies efficiently neutralize SARS-CoV-2. Science Published online November 5, 2020.

Claims

Claims

1. A polypeptide selected from peptides of sequence SEQ ID NO. 1, SEQ ID NO. 2, SEQ ID NO. 7, and SEQ ID NO.

10.

2. A composite polypeptide comprising a plurality of polypeptides according to claim 1 or a polypeptide according to claim 1 covalently linked by its amino acid residue at the N-terminus to a peptide of sequence SEQ ID NO.

54.

3. The composite polypeptide according to claim 2, the composite polypeptide being selected from peptides of sequence SEQ ID NO. 11, SEQ ID NO. 12, SEQ ID NO. 13, SEQ ID NO. 14 and SEQ ID NO.

15.

4. A pharmaceutical composition comprising a polypeptide according to claim 1 or a composite polypeptide according to claim 2 or 3, in combination with at least one pharmaceutically or physiologically acceptable carrier.

5. A polypeptide according to claim 1, a composite polypeptide according to claim 2 or 3, or a pharmaceutical composition according to claim 4, for use as a medicament.

6. A polypeptide according to claim 1, a composite polypeptide according to claim 2 or 3, or a pharmaceutical composition according to claim 4, for use in the treatment and / or prevention in an individual of a condition caused by infection with a virus of the species SARS-CoV.

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