FR3127756A1 - Neutralizing polypeptides and their applications - Google Patents

Abstract

Neutralizing Polypeptides and Their Applications The present invention aims to provide new polypeptides of formula (I) and pharmaceutical compositions comprising such polypeptides. These new polypeptides of formula (I) or pharmaceutical compositions which 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. Figure for abstract: None

Description

Neutralizing polypeptides and their applications

The present description relates to new artificial polypeptides, in particular new alpha-helical repeat proteins of the HEAT type (αRep). The present description also relates to the use of these novel polypeptides as medicaments, in particular for the treatment and prevention of diseases and/or conditions caused by infection with a virus of the SARS-CoV species, in particular SARS -CoV-2.

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

Although their replication cycle varies greatly from one species to another, it is generally accepted that the life cycle of viruses comprises six fundamental stages: attachment, penetration, stripping, replication, assembly and the Liberation.

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

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

- Group I: double-stranded DNA virus (dsDNA);

- Group II: single-stranded DNA virus (sDNA);

- Group III: double-stranded RNA virus (dsRNA);

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

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

- Group VI: single-stranded RNA virus having DNA intermediates (sRNA-TR); And

- Group VII: double-stranded DNA viruses with RNA intermediates (dsDNA-TR).

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

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

The World Health Organization (WHO) has officially declared the COVID-19 pandemic a public health emergency of international concern. This new coronavirus spreads mainly through the respiratory tract and causes acute respiratory illnesses. The elderly and those with underlying illnesses are susceptible to infection and prone to serious outcomes, which may be associated with acute respiratory distress syndrome (ARDS).

This coronavirus is a single-stranded, positive-sense, approximately 30 kilobase RNA virus that replicates in the cytoplasm of host cells. This virus is enveloped and comprises, on its surface, peplomeric structures called spicules made up of the Spike (S) protein.

The Spike or S protein is a membrane glycoprotein (200-220 kDa) which is in the form of spicules or "Spike" emerging from the surface of the viral envelope. This surface protein binds to the cell receptor ACE2 which is expressed in many tissues. It contains 2 subunits (S1 and S2), S1 including the receptor binding domain (RBD) containing the receptor binding motif (RBM) and S2 containing the fusion peptide allowing the induction of the fusion of the viral envelope with the cell membrane. Protein S is the main target of the neutralizing antibody response.

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 virus entry into target cells in the lungs and other tissues by targeting the S protein and primarily its RBD domain (Spike protein S1 subunit receptor binding domain).

This neutralization of the S protein can be done, in particular, thanks to natural or artificial proteins, such as:

- human monoclonal antibodies, the cost of which is substantial and reserved for very specific cases,

- derivatives of VHH (Recombinant Llama Antibodies) which should be used by chimerizing VHH to make VHH-Fc that can be recognized by the patient's immune system,

- DARPins (Designed Ankyrin Repeat Proteins), and

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

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

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

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

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

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

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

There is a need for new proteins with strong neutralizing activity against a virus of the SARS-CoV species, in particular SARS-CoV-2, causing little or no immune reaction in an individual.

The present invention aims to meet all or part of these needs.

Explanation of this description

The inventors have developed new peptides for treating and/or preventing an 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 αReps, as defined in the present description had a neutralizing activity for the SARS-CoV-2 virus. Surprisingly, and contrary to the teaching of the prior art concerning human monoclonal antibodies (Barnes 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. Trends in Microbiology 29, 195-203; Güttler et al. EMBO J. e107985, 2021; Hanke et al. Nat. Struct. Mol. Biol. 27, 846–854, 2020; Ma et al. J Virol . 95:e02438-20, 2021; Schoof et al. Science 370, 1473–1479, 2020; Wrapp et al. Cell 181, 1004–1015.e1015, 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 strong affinity to the RBD domain of the S1 subunit of the S protein of viruses of the species SARS-CoV, including αReps 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. Moreover, due to their small size (for example, 170 amino acids for the C2 polypeptide), the artificial polypeptides of the present description are not very immunogenic, or even non-immunogenic. These new compounds are alpha-helical repeat proteins of the HEAT type (αReps) which have the ability 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.

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

Thus the present invention aims to provide new polypeptides and pharmaceutical compositions comprising such polypeptides. These new polypeptides or pharmaceutical compositions which can be implemented 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 this description

According to one of its objects, the present description relates to 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] - X1 - X2 -VR- X3 - X4 -AA- X5 -ALG- X6 -I - COOH (II)

in which :

- X1 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);

- X2 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), N (Asparagine), ;

- 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);

- 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);

- 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

- X6 is an amino acid chosen from K (Lysine), Q (Glutamine), E (Glutamic Acid).

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

- X1, 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);

- 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);

-X3,this one 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);

- 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);

-X5,this one 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

- X6 , the latter being an amino acid chosen from K (Lysine), Q (Glutamine), E (Glutamic Acid).

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

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.

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

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

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

According to certain particular embodiments, the polypeptide of formula (I) can 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.

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 to the N-terminal end to a peptide of sequence SEQ ID NO.54.

According to certain embodiments, a composite polypeptide according to the description can consist of a dimer or a trimer of a polypeptide of formula (I) as described in the present description.

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

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

According to certain other preferred embodiments of a composite polypeptide according to the present description, the composite polypeptide can 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.

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.

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 .

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 infection with a virus of the SARS-CoV species, specifically SARS-CoV-2.

According to another of its objects, the present description also relates to a method for treating and/or preventing a condition caused by an infection by a virus of the SARS-CoV species, in particular SARS-CoV-2, in individual in need, 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.

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 medicinal product intended for 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.

shows that αReps C2, C12, F9, G1, H10 and H12 have low dissociation rates unlike αReps C7, D7 and F7. There represents the binding of αReps H7 (negative control), C7, H10, C12, F9, F7, D7, G1 and C2 concentrated at 1 μM on the RBD domain of the SARS-CoV-2 virus by bi-layer interferometry. Abscissa : The time in seconds. Y-axis: Thickness of the bi-layer on the sensor (expressed in nm)

And show that αReps C2 and F9 have high binding affinity for the RBD domain and the S1 subunit (the N-ter domain of the S protein) of SARS-CoV-2. THE And represent the binding of the αReps C2, F9 and of the F9-C2 dimer on the RBD domain of the S1 subunit analyzed by bi-layer interferometry. 2A represents the binding of the αRep C2 to the RBD domain. 2B represents the binding of αRep C2 to the S1 subunit. The 2C represents the binding of the αRep F9 to the RBD domain. The 2D represents the binding of the αRep F9 on the S1 subunit. There represents the binding of the composite αRep F9-C2 to the S1 subunit. Abscissa : The time in seconds. Y-axis : Thickness of the bi-layer on the sensor (expressed in nm).

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

show that the composite αRep F9-C2 neutralizes the infection of HEK 293T cells by pseudotyped MLV particles carrying the S protein or by the SARS-CoV-2 virus. Three biological replicates per concentration. The error bars represent the standard deviation from the mean.
4A represents the inhibition of the infection of HEK-293T cells expressing ACE2 by pseudotyped particles of MLV with the S protein of SARS-CoV-2 in the presence of the composite αRep F9-C2 and αReps F9, C2 and H7 (negative control). Abscissa : HEK-293T cells in the presence of mixtures of (a) 100 nM (black), (b) 10 nM (dark gray), (c) 1 nM (medium gray) of αRep with particles pseudo-typed with the SARS-CoV-2 protein S or (d) MLV-like particle infected cells carrying Vesicular Stomatitis Virus G protein (VSVG – light gray) with αReps at a concentration of 3 μM ( infection inhibition specificity control). Y-axis : Percentage infection rate of HEK 293T cells by particles pseudotyped with protein S (SARS-CoV-2) or G (VSVG).
4B represents inhibition of infection of Vero-E6 cells by SARS-CoV-2 viruses. Abscissa : Concentration in μM of αReps C2, F9-C2, F9+C2 and H7 in the culture medium of infected cells. Cells were infected without αRep (virus alone) or uninfected (cells alone) . Y-axis : Viability of Vero-E6 cells infected with the SARS-CoV-2 virus in the presence of αReps (in arbitrary luminescence units).

shows that the composite αReps C2-foldon and F9-foldon have a similar or even superior neutralizing activity on SARS-CoV-2 infection compared to the αReps F9 and C2 alone and F9-C2. Three biological replicates per concentration were performed. Error bars represent the standard deviation from the meanAbscissa:Concentration in µM of αReps C2-foldon (■), F9-foldon (star), F9-C2 (▲), F9 (▼), C2 (●) and H7 (○) in the culture medium of cells infected with the SARS-CoV-2 . Ordered: Viability of Vero-E6 cells infected with the SARS-CoV-2 virus in the presence of αReps (in arbitrary luminescence units).

And show that the αReps F9, C2 and F9-C2 have a neutralizing activity on mutants of the S protein of SARS-CoV-2. The four variants analyzed (alpha, beta, gamma and kappa) are all more sensitive to the neutralization of the composite αRep F9-C2 than the αReps F9 and C2 alone, underlining the cooperative effect associated with the fusion of F9 and C2 . There6arepresents the inhibition of the infection of HEK-293T cells expressing ACE2 by retroviruses pseudotyped with the S protein of SARS-CoV-2 (from the Wuhan-Hu-1 isolate). Also shown is the inhibition of infection of HEK-293T cells expressing ACE2 by pseudotyped retroviruses with protein S mutants: N501Y (6b), K417N, E484K, N501Y (6c), K417T, E484K, N501Y (6d) and L452R, E484Q (6th). Three biological replicates per concentration were performed. The 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 of αRep with particles pseudo-typed with the S protein of SARS-CoV-2, and VSVG (control of specificity of the inhibition of infection): Cells infected with pseudo- MLV particles carrying the G protein of the vesicular stomatitis virus (VSVG) with the αReps at a concentration of 3 mM.Ordered: Percentage infection rate of HEK 293T cells by particles pseudotyped with protein S (SARS-CoV-2) or G (VSVG).

show that composite αRep F9-C2 reduces infection by SARS-CoV-2 in vivo compared to control αRep H7 in a hamster model.
7A represents the relative expression of SARS-CoV-2 protein E reflecting the presence of the virus in the presence of αRep H7 (white dot) or F9-C2 (black dot) in the olfactory mucosa and day-to-day lungs 1 (D1) or day 3 (D3) post infection. Abscissa : Sampling on D1 and D3 post-infection of the olfactory mucosa and lungs of hamsters having received αRep H7 or F9-C2 by nasal inoculation 1 hour before infection with the SARS-CoV-2 virus. Y-axis : Relative log expression of SARS-CoV-2 virus E protein.
7B represents the viral titer of nasal smears reflecting the production of the SARS-CoV-2 virus by the nasal cavity of infected hamsters on 3 days post infection. Abscissa : Days post-infection with SARS-CoV-2 (dpi). Y-axis : Viral titre of nasal smears (log TCID ₅₀ ) of hamsters having received αRep H7 or F9-C2 by nasal inoculation 1 h before infection with the SARS-CoV-2 virus.

Claims (10)

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 ₁ -X ₂ -V-R-X ₃ -X ₄ -A-A-X ₅ -A-L-G-X ₆ -I-COOH(II)
in which :
-X ₁ 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);
-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), 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 selected 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 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
-X ₆ is an amino acid chosen from K (Lysine), Q (Glutamine), E (Glutamic Acid). The polypeptide of formula (I) according to claim 1, wherein the SBP of formula(II)understand :
-X ₁ 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);
-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 selected 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 selected 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); And
-X ₆ is an amino acid chosen from K (Lysine), Q (Glutamine), E (Glutamic Acid). The polypeptide of formula (I) according to any one of the preceding claims, Nt being 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. The polypeptide of formula (I) according to any one of the preceding claims, Ct consisting of a peptide of sequence SEQ ID NO.18. The polypeptide of formula (I) according to any one of the preceding claims, the polypeptide of formula (I) being 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. A composite polypeptide comprising a plurality of polypeptides of formula (I) according to any one of the preceding claims or a polypeptide of formula (I) covalently linked by its amino acid residue at the N-terminal end to a peptide of sequence SEQ ID NO. 54. The composite polypeptide according to claim 6, the composite polypeptide being 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. A pharmaceutical composition comprising a polypeptide of formula (I) according to any one of Claims 1 to 5 or a composite polypeptide according to Claim 6 or 7, in combination with at least one pharmaceutically or physiologically acceptable vehicle. A polypeptide of formula (I) according to any one of claims 1 to 5, a composite polypeptide according to claim 6 or 7, or a pharmaceutical composition according to claim 8, for use as a medicament. A polypeptide of formula (I) according to any one of claims 1 to 5, a composite polypeptide according to claim 6 or 7, or a pharmaceutical composition according to claim 8, for use in the treatment and/or prevention in an individual of a condition caused by infection with a virus of the SARS-CoV species.