WO2021233885A1 - Peptides mimotopes de la protéine spike du virus sars-cov-2 - Google Patents

Peptides mimotopes de la protéine spike du virus sars-cov-2 Download PDF

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WO2021233885A1
WO2021233885A1 PCT/EP2021/063091 EP2021063091W WO2021233885A1 WO 2021233885 A1 WO2021233885 A1 WO 2021233885A1 EP 2021063091 W EP2021063091 W EP 2021063091W WO 2021233885 A1 WO2021233885 A1 WO 2021233885A1
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seq
peptide
amino acid
cov
sars
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PCT/EP2021/063091
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English (en)
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Anton Alekseevich TIKHONOV
Dominique Charron
Elvenn LORET
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Synthetic Vaccines Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
    • A61K2039/575—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 humoral response
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011—Details
    • C12N2770/20011—Coronaviridae
    • C12N2770/20034—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

  • the present invention relates to 3D mimotope peptides of the spike protein (S-protein) from the SARS-CoV-2 virus.
  • the peptides according to the invention may be useful to prepare a pharmaceutical composition, such as, e.g ., a vaccine composition.
  • the peptides according to the invention may be useful to prevent and/or treat an infection by the SARS-CoV-2 virus, and to diagnose said infection.
  • SARS-CoV-2 virus for Severe Acute Respiratory Syndrome Coronavirus 2
  • Coronavirus 2 The recently identified SARS-CoV-2 virus (for Severe Acute Respiratory Syndrome Coronavirus 2) is the infectious agent causing the pandemic COVID-19 disease that has spread worldwide by the end of 2019, early 2020.
  • the most frequent symptoms of the COVID-19 disease are fever, cough, and shortness of breath.
  • Other symptoms include fatigue, myalgia, gastrointestinal symptoms, chemosensory dysfunction (such as, e.g. , anosmia and dysgeusia), viral encephalitis, myocarditis and cutaneous lesions (such as, e.g. , erythematous rash, widespread urticaria).
  • RT-PCR bronchoalveolar lavage
  • Chest Computerized Tomography has been shown to be a useful tool for the diagnosis of COVID-19. If chest CT appears to offer a good sensitivity for COVID-19 diagnosis, it lacks however in specificity.
  • Rapid tests have also been developed with the idea of a point-of-care approach, offering rapid results (within 10-30 minutes).
  • Two types of rapid tests have been developed to date: rapid antigen tests, which involve the direct detection of SARS-CoV-2 antigen on respiratory samples such as naso-pharyngeal swabs.
  • Initial test validation has shown a high specificity (100%), but lower sensitivity (56-60%);
  • - rapid antibody tests which are immune-chromatographic assays developed for point-of-care detection of circulating SARS-CoV-2 antibodies. The tests provide rapid but only qualitative information (presence or not of antibodies).
  • the SARS-CoV-2 virus is a b-coronavirus that belongs to the Coronaviridae family (coronavirus).
  • the coronavirus family are represented by viruses from the subgroups alpha (a), beta (b), gamma (g), and delta (d) coronavirus.
  • the four ‘common human coronaviruses’ are 229E (a coronavirus), NL63 (a coronavirus), OC43 (b coronavirus) and HKU1 (b coronavirus).
  • b-coronaviruses also include SARS-CoV and MERS-CoV, other acute-lung-injury causing coronaviruses.
  • SARS-CoV-2 is most closely related to SARS-CoV, sharing roughly 80% identity at a nucleotide level.
  • Coronaviruses have large (26-32 kbs) single-stranded, positive-sense RNA genomes, which are encapsulated by a crown-like appearance under an electron microscope, due to the presence of spike glycoproteins on the envelope.
  • the viral particles contain four main structural proteins, namely the spike (S-protein), membrane (M-protein), envelope (E-protein), and nucleocapsid (N-protein) proteins.
  • Viral binding to the cells occurs via the interaction between the receptor-binding domain (RBD) from the S-protein of SARS-CoV-2, and Angiotensin-converting enzyme 2 (ACE2), which is expressed at the surface of lung alveolar epithelial cells, enterocytes of the small intestine, in arterial and venous endothelial cells, and in arterial smooth muscle cells of multiple organs.
  • RBD receptor-binding domain
  • ACE2 Angiotensin-converting enzyme 2
  • viral replication would involve viral RNA translation, assembly of viral replicase transcription complexes, viral RNA synthesis, assembly of virions within the endoplasmic reticulum-Golgi apparatus intermediate compartment, and transport of these to the cell surface inside vesicles.
  • the newly formed infectious virions are then released from the host cell by exocytosis.
  • Consensual evidence indicates that human to human transmission of SARS-CoV-2 virus is principally air-borne mediated, through infectious droplets.
  • US2010150923 disclosed fusion proteins of recombinant SARS-CoV structural proteins, their production and use thereof for vaccine production.
  • US20060110758 disclosed methods for locating critical portions or sites on the S- protein of SARS-CoV responsible for the viral infection that SARS.
  • W02005028497 disclosed peptides that bind to the cellular receptor for the SARS S- protein.
  • a first aspect of the invention pertains to a peptide comprising an amino acid sequence having at least about 75% sequence identity to SEQ ID NO: 3 or SEQ ID NO: 4, a structural variant thereof, or a functional variant thereof that binds to the ACE2 receptor, in which the cysteines C497 and C507 of sequence SEQ ID NO: 3 or SEQ ID NO: 4 are invariable, said amino acid positions being defined with respect to the amino acid sequence SEQ ID NO: 1.
  • the peptide is a cyclic peptide. In some embodiments, the peptide is a mimotope peptide with a 3D structure. In certain embodiments, the mimotope peptide binds to the ACE2 receptor or a domain thereof that specifically binds to a region, in particular a loop, on the SARS-CoV-2 spike protein involved in the interaction between a SARS-CoV-2 spike protein with an ACE2 receptor. In some embodiments, the peptide comprises an amino acid sequence selected in the group consisting of SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 11.
  • cysteines C497 and C507 of sequence SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11 are covalently linked, wherein said amino acid positions are defined with respect to the amino acid sequence SEQ ID NO: 1.
  • the covalent link is a disulfide bond.
  • the structural and/or functional variant of the peptide comprising an amino acid sequence of SEQ ID NO: 4 comprises one or more amino acid substitutions selected in the group consisting of Q498R, Q498N, Q498Y, Q498H, Q498F or Q498T; P499T, P499I or P499Q; T500I, T500S; N501Y, N501Q, N501D, N501S or N501T; G502A; V503A, V503L or V503I; G504A; Y505F, Y505W or Y505H; Q506N, Q506H or Q506P; Y508F or Y508W; R509K or R509H, wherein said amino acid positions are defined with respect to the amino acid sequence SEQ ID NO: 1.
  • the structural and/or functional variant of the peptide comprising an amino acid sequence of SEQ ID NO: 3 comprises one or more amino acid substitutions selected in the group consisting of E484K, E484Q, E484D, E484P or E484T; G485A, G485R or G485V; F486Y, F486W, F486L or F486P; N487Q; S488T; Y489F or Y489W; F490Y, F490W or F490K; P491L; L492I, L492V or L492A; Q493N, Q493Y, Q493R, Q493L or Q493A; S494T, S494P, S494D, S494R or S494G; Y495F or Y495W; G496A; Q498R, Q498N, Q498Y, Q498H, Q498F or Q
  • Another aspect of the invention relates to a nucleic acid encoding peptide according to the disclosure herein.
  • the invention further relates to a composition, in particular a vaccine composition, comprising (i) a peptide according to the invention and (ii) an acceptable vehicle.
  • a composition in particular a vaccine composition, comprising (i) a peptide according to the invention and (ii) an acceptable vehicle.
  • the composition is lyophilized.
  • Another aspect of the invention relates to a peptide or a composition according to the disclosure herein for use for eliciting an immune response against a virus of the SARS- CoV-2 coronavirus family.
  • a still other aspect of the invention relates to a peptide or a composition according to the invention for use for preventing and/or treating an infection by a virus of the SARS- CoV-2 coronavirus family.
  • the peptide or the composition is to be administered orally, parenterally, subcutaneously, intramuscularly, intradermally, intramucosally, intravenously or intranasally, preferably intradermally.
  • “Comprise” is intended to mean “contain”, “encompass” and “include”. In some embodiments, the term “comprise” also encompasses the term “consist of’.
  • SARS-CoV-2 virus is intended to refer to the pathogenic microorganism, in particular the virus, that is responsible of the COVID-19 viral infection.
  • S-protein refers to one of the structural proteins from the SARS-CoV-2 virus, that give the characteristic shape to the virus under electronic microscopy.
  • the reference sequence of the S-protein is represented by the amino acid sequence SEQ ID NO: 1.
  • Protein or “polypeptide” refers to a linear polymer of amino acids linked together by peptide bonds.
  • “Invariable amino acid” is intended to refer to an amino acid that is not substituted with another amino acid residue at a given position within an amino acid sequence.
  • “Structural variant”, when referred to the peptide according to the invention, is intended to refer to a variant or derivative of the peptide that shares a similar amino acids sequence and/or 3D structure.
  • the term “having a similar amino acids sequence and/or 3D structure” is intended to mean that the variant of the peptide differs from the reference peptide in that it possesses one or more substituent(s) that does/do not alter the overall structure.
  • “Functional variant”, when referred to the peptide according to the invention, is intended to refer to a variant or derivative of the peptide that shares an equivalent biological physiological function, /. e. , the capacity to bind to an ACE2 receptor in vitro and/or in vivo , under suitable conditions.
  • amino acid conservation when used in a relationship between the sequences of two or more polypeptides sequences, refers to the degree of amino acid sequence relatedness between a given region in said polypeptides sequences.
  • amino acid conservation for a given amino acid position may refer to either a unique amino acid residue or to a related amino acid residue.
  • hydrophobic amino acid residues such as Leu (L), I1e (I), Val (V) may be considered as related amino acids. It is the same with positively charged amino acid residues Lys (K), Arg (R), His (H) and to negatively charged amino acid residues such as Glu (E) and Asp (D).
  • conserved amino acid residues within a region from two or more polypeptides may be referred to as a “consensus sequence”.
  • Cyclic peptide refers to a peptide in which the lateral chains of 2 non-contiguous amino acid residues are covalently linked.
  • the covalent link is a disulfide bridge in between 2 -SH groups belonging to 2 non-contiguous cysteine residues.
  • isolated peptide refers to a peptide that is removed from the environment in which it has been synthesized.
  • Synthetic peptide refers to a peptide that does not exist in nature and/or is synthesized chemically or by the mean of recombinant technologies.
  • Immunogenic peptide refers to a peptide capable of eliciting an immune response in an individual upon contact with said individual.
  • “Mimotope peptide” refers to a peptide, in particular a synthetic peptide, that mimics epitopes of an antigen found in nature.
  • the mimotope may be represented by a linear peptide, and preferably a peptide with a 3D structure.
  • “Sequences identity”, when used in a relationship between the sequences of two or more polypeptides or of two or more nucleic acid sequences refers to the degree of sequence relatedness between polypeptides or nucleic acid sequences (respectively), as determined by the number of matches between strings of two or more amino acid residues or of two or more nucleotides, respectively.
  • Identity measures the percent of identical matches between the smaller of two or more sequences with gap alignments (if any) addressed by a particular mathematical model or computer program (i.e., “algorithm”).
  • Identity of related polypeptides or nucleic acid sequences can be readily calculated by known methods. Such methods include, but are not limited to, those described in Computational Molecular Biology, Lesk, A. M., ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, D. W., ed., Academic Press, New York, 1993; Computer Analysis of Sequence Data, Part 1, Griffin, A. M., and Griffin, H.
  • Preferred methods for determining identity are designed to give the largest match between the tested sequences. Methods of determining identity are described in publicly available computer programs. Preferred computer program- based methods for determining identity between two sequences include the GCG program package, including GAP (Devereux et al ., Nucl. Acid. Res.
  • the “identity” refers to a parameter measured over the entire length of the sequence to which it refers.
  • the nucleic acid identity percentage may be determined using the CLUSTAL W software (version 1.83) the parameters being set as follows: for slow/accurate alignments: (1) Gap Open Penalty: 15; (2) Gap Extension Penalty: 6.66; (3) Weight matrix: IUB; for fast/approximate alignments: (4) K-tuple (word) size: 2; (5) Gap Penalty: 5; (6) No. of top diagonals: 5; (7) Window size: 4; (8) Scoring Method: PERCENT.
  • the amino acid identity percentage may also be determined using the CLUSTAL W software (version 1.83) the parameters being set as follows: for slow/accurate alignments: (1) Gap Open Penalty: 10.00; (2) Gap Extension Penalty: 0.1; (3) Protein weight matrix: BLOSUM; for fast/approximate alignments: (4) Gap penalty: 3; (5) K-tuple (word) size: 1; (6) No. of top diagonals: 5; (7) Window size: 5; (8) Scoring Method: PERCENT.
  • Carrier protein refers to a protein that displays the peptide according to the invention at its surface, when the peptide is conjugated with the carrier protein.
  • conjugated is meant that the peptide and the carrier protein are covalently associated.
  • Linker refers to a stretch of chemical or amino acid sequence that physically separate 2 domains or moieties.
  • the peptide and the carrier protein are conjugated by the mean of a linker” is intended to mean that the peptide and the carrier protein are indirectly covalently associated through the linker.
  • Immunogenic composition refers to a composition that is capable of eliciting an immune response in an individual upon contact with said individual.
  • Vaccine composition refers to a composition comprising one or more antigens and/or epitopes suitable for triggering an immune response against these antigens and/or epitopes in an individual that is the recipient of said composition.
  • adjuvant refers to a compound or a combination of compounds that potentiates an immune response within a vaccine composition.
  • the adjuvant is used with a vaccine composition and thus potentiates the immune response towards a viral infection.
  • an adjuvant may increase the number of lymphocytes; increase the activation of lymphocytes; increase the fitness of lymphocytes; and/or increase the survival of lymphocytes.
  • “Infection” refers to the physiological events that arise upon establishment of one or more pathogenic agents, such as viruses, in or on the body of a living organism, such as an animal. An infection may be characterized by one or more symptom(s) that may be monitored by procedures well known in the state of the art.
  • “Inhibit the interaction” refers to the fact of preventing or severely affecting the occurrence of a binding event between 2 domains or moieties that are capable of binding to one another.
  • “inhibition of the interaction of the peptide according to the invention and an ACE2 receptor” is intended to mean that the peptide and the ACE2 receptor are not significantly binding to one another.
  • Treating” or “treatment” or “alleviation” refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) the targeted pathologic infection by a SARS-CoV-2 virus.
  • Those in need of treatment include those already with said infection as well as those prone to develop the disorder or those in whom the infection is to be prevented.
  • An individual is successfully "treated” for an infection by a SARS-CoV-2 virus, if, after receiving a therapeutic amount of the peptide according to the present invention, the individual shows observable and/or measurable reduction in, or absence of, one or more of the symptoms associated with said viral infection; reduced morbidity and mortality, and improvement in quality of life issues.
  • the above parameters for assessing successful treatment and improvement in the disease are readily measurable by routine procedures familiar to physician or authorized personnel.
  • Preventing refers to keeping from happening, and/or lowering the chance of the onset of, or at least one adverse effect or symptom of, an infection by a SARS-CoV- 2 virus.
  • “Therapeutic effective amount” refers to the level or the amount of the active agent that is aimed at, without causing significant negative or adverse side effects to the target, (1) delaying or preventing the onset of an infection by a SARS-CoV-2 virus; (2) slowing down or stopping the progression, aggravation, or deterioration of one or more symptoms of an infection by a SARS-CoV-2 virus; (3) bringing about ameliorations of the symptoms of an infection by a SARS-CoV-2 virus; (4) reducing the severity or incidence of an infection by a SARS-CoV-2 virus; or (5) curing an infection by a SARS-CoV-2 virus.
  • a therapeutically effective amount may be administered prior to the onset of an infection by a SARS-CoV-2 virus, for a prophylactic or preventive action.
  • the therapeutic effective amount may be administered after the onset of an infection by a SARS- CoV-2 virus, for a therapeutic action, in particular for vaccination purposes.
  • a therapeutic effective amount of the composition is an amount that is effective in reducing at least one symptom of an infection by a SARS-CoV-2 virus.
  • “Pharmaceutically acceptable vehicle” refers to a vehicle that does not produce any adverse, allergic or other unwanted reactions when administered to an animal individual, preferably a human individual. It includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. For human administration, preparations should meet sterility, pyrogenicity, general safety, quality and purity standards as required by regulatory Offices, such as, e.g ., the Food and Drug Administration (FDA) in the United States or the European Medicines Agency (EMA) in the European Union.
  • FDA Food and Drug Administration
  • EMA European Medicines Agency
  • “Individual” is intended to refer to an animal individual, preferably a mammalian individual, more preferably a human individual.
  • pets such as dogs, cats, guinea pigs; animals of economic importance such as cattle, sheep, goats, horses, monkeys.
  • an individual may be a “patient”, i.e. a warm-blooded animal, more preferably a human, who/which is awaiting the receipt of, or is receiving medical care or was/is/will be the object of a medical procedure, or is monitored for the development of an infection by a SARS-CoV-2 virus.
  • the individual is an adult (for example a human subject above the age of 18). In another embodiment, the individual is a child (for example a human subject below the age of 18). In one embodiment, the individual is a male. In another embodiment, the individual is a female.
  • the coronavirus S-protein is the structural protein responsible for the crown-like shape of the SARS-CoV-2 viral particles, from which the original name “coronavirus” was coined.
  • the approximately 1,200-amino acid long S-protein belongs to class-I viral fusion proteins and contributes to the cell receptor binding, tissue tropism and pathogenesis (Lu et al ., Trends Microbiol. 23(8):468-78 (2015); Millet and Whittaker, PNAS, 111(42): 15214-9 (2014)).
  • SP Signal peptide
  • NTD N-terminal domain
  • RBD receptor-binding domain
  • FP fusion peptide
  • IFP internal fusion peptide
  • HR1/2 heptad repeat 1/2
  • TM transmembrane domain
  • the main region of interaction with the putative cellular receptor counter-part is formed by fifteen residues ordered into a beta-sheet conformation surrounded by two capping loops (Ortega etal. , EXCLIS J. 19:410-417 (2020)).
  • the domain of the S-protein that is responsible for ACE2 receptor interaction has been identified as forming a loop, from amino acid residue E484 to amino acid residue R509, with respect to SEQ ID NO: 1, and having the following amino acid sequence: EGFNCYFPLQSYGFQPTNGVGYQPYR (SEQ ID NO: 2) (Ortega et al. , EXCLIS J. 19:410-417 (2020); Walls et al., Cell. 180:1-12 (2020)).
  • references of the amino acid residues in the peptide according to the instant invention are made as compared to the position of the corresponding amino acid residues in the full-length polypeptide of sequence SEQ ID NO: 1.
  • the inventors designed a mimotope peptide starting from the peptide SEQ ID NO: 2. They found that the 3D structure of the peptide SEQ ID NO: 2 could be conserved and further stabilized by performing 3 substitutions, namely C488S, F497C and P507C, so as to create a cyclic peptide of the following amino acid sequence: EGFNSYFPLQSYGCQPTNGVGYQCYR (SEQ ID NO: 3), wherein the 2 cysteine residues are covalently linked by a disulfide bridge.
  • stabilization of the 3D structure of the cyclic peptide of sequence SEQ ID NO: 3 is provided by a disulfide bond that covalently binds cysteines C497 and C507, wherein said amino acid positions are defined with respect to the amino acid sequence SEQ ID NO: 1.
  • the inventors consider that a peptide comprising the amino acid sequence CQPTNGVGYQC (SEQ ID NO: 4) is still capable of binding to the ACE2 receptor.
  • a first aspect of the invention relates to a peptide comprising an amino acid sequence having at least about 75% sequence identity to SEQ ID NO: 3 or SEQ ID NO: 4, a structural variant thereof, or a functional variant thereof that binds to the ACE2 receptor.
  • Another aspect of the invention relates to a peptide comprising an amino acid sequence having at least about 75% sequence identity to SEQ ID NO: 3 or SEQ ID NO: 4, a structural variant thereof, or a functional variant thereof that binds to the ACE2 receptor, in which the two cysteine residues in SEQ ID NO: 3 or SEQ ID NO: 4 are invariable.
  • the peptide according to the invention invariably comprises two cysteines at positions C497 and C507, wherein said amino acid positions are defined with respect to the amino acid sequence SEQ ID NO: 1.
  • the peptide cannot be represented by the full-length sequence of the S-protein of amino acid sequence SEQ ID NO: 1, or the domain of the S-protein that is responsible for ACE2 receptor interaction of amino acid sequence SEQ ID NO: 2.
  • a further aspect of the invention relates to a peptide comprising an amino acid sequence having at least about 75% sequence identity to SEQ ID NO: 3 or SEQ ID NO: 4, a structural variant thereof, or a functional variant thereof that binds to the ACE2 receptor, in which the cysteines C497 and C507 of sequence SEQ ID NO: 3 or SEQ ID NO: 4 are invariable, said amino acid positions being defined with respect to the amino acid sequence SEQ ID NO: 1.
  • 75% sequence identity includes 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% sequence identity.
  • the term “invariable”, when referring to an amino acid residue, is intended to mean that the specified amino acid residue, at a given position within the amino acid sequence, is not substituted with another amino acid residue. In other words, the specified amino acid residue, at a given position, is exactly conserved.
  • the peptide does not comprise any further cysteine residue, except for the two cysteine residues.
  • the peptide comprises an amino acid sequence having at least about 80% sequence identity to SEQ ID NO: 3 or SEQ ID NO: 4, a structural variant thereof, or a functional variant thereof that binds to the ACE2 receptor.
  • the peptide comprises an amino acid sequence having at least about 85% sequence identity to SEQ ID NO: 3 or SEQ ID NO: 4, a structural variant thereof, or a functional variant thereof that binds to the ACE2 receptor.
  • the peptide comprises an amino acid sequence having at least about 90% sequence identity to SEQ ID NO: 3 or SEQ ID NO: 4, a structural variant thereof, or a functional variant thereof that binds to the ACE2 receptor. In one embodiment, the peptide comprises an amino acid sequence having at least about 95% sequence identity to SEQ ID NO: 3 or SEQ ID NO: 4, a structural variant thereof, or a functional variant thereof that binds to the ACE2 receptor.
  • amino acid sequence comprises at least 11 amino acid residues.
  • at least 11 amino acid residues includes 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,
  • the peptide comprises from 11 to about 50 amino acid residues.
  • the term “11 to about 50 amino acid residues” includes 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 and 50 amino acid residues.
  • the peptide according to the invention and a structural and/or functional variant thereof, binds to an ACE2 receptor, preferably to a human ACE2 receptor.
  • ACE2 refers to Angiotensin I Converting Enzyme 2, Angiotensin I Converting Enzyme (Peptidyl-Dipeptidase A) 2, Angiotensin-Converting Enzyme Homolog, Angiotensin-Converting Enzyme 2, ACE-Related Carboxypeptidase, Metalloprotease MPROT15, Peptidyl-Dipeptidase A, ACEH, EC 3.4.17.23 and EC 3.4.17.
  • binding of peptides according to the invention, or a structural and/or functional variant thereof, to the ACE2 receptor may be assessed by the mean of any suitable method available in the state of the art, or a method adapted therefrom.
  • binding assay may be performed by Biacore; Isothermal titration calorimetry (ITC); native electrochromatography; co-separation-based techniques, such as for example co-immunoprecipitation, GST pull-down and the like; fluorescence- based assays, such as for example FRET, BiFC and the like; surface plasm on resonance-based assay; genetic reporter-based assays such as for example, yeast-2- hybrid, phage display and the like.
  • the peptide is a cyclic peptide.
  • the peptide has a 3D structure.
  • the 3D structure of the peptides according to the invention may be assessed by the mean of any suitable method available in the state of the art, or a method adapted therefrom.
  • secondary structures such as beta-turns, beta-sheets and alpha- helixes, and 3D structures, resulting from the further folding of these secondary structures, may be assessed by Dynamic light scattering (DLS); Static light scattering (SLS); Circular Dichroism (CD), including UV (Ultra Violet) CD, IR (Infrared) CD and vibrational CD; Isothermal titration calorimetry (ITC); X Ray diffraction; 2D nuclear magnetic resonance (NMR); and the like.
  • DLS Dynamic light scattering
  • SLS Static light scattering
  • CD Circular Dichroism
  • ITC Isothermal titration calorimetry
  • X Ray diffraction 2D nuclear magnetic resonance (NMR); and the like.
  • the peptide is a mimotope peptide.
  • the peptide is a mimotope peptide with a 3D structure.
  • the mimotope peptide binds to the ACE2 receptor or a domain thereof that specifically binds to a region, in particular a loop, on the SARS-CoV-2 spike protein involved in the interaction between a SARS-CoV-2 spike protein with an ACE2 receptor.
  • the region on the SARS-CoV-2 spike protein involved in the interaction between a SARS-CoV-2 spike protein (S-protein) with an ACE2 receptor is a loop.
  • the ACE2 receptor is a mammalian ACE2 receptor, preferably a human ACE2 receptor. In one embodiment, the ACE2 receptor is a human ACE2 receptor.
  • amino acid sequence as defined herein may comprise any amino acid substitution as described in the state of the art, provided the amino acid sequence retains its 3D structure upon cyclization and its capacity to bind to the ACE2 receptor, except mutations of the two cysteine residues and mutation of any amino acid residue with a cysteine residue.
  • amino acid substitution as described in the state of the art refers to any of the mutations that have been and/or are to be identified, e.g ., in the so- called UK (B.l.1.7 lineage), Brazilian (P.l lineage), Indian (B.1.617 lineage), South African (B.1.351 lineage), Nigerian (B.1.525 lineage), Californian (B.1.427 lineage) or West Coast (B.1.429 lineage) variants of the SARS-CoV-2 S-protein.
  • the amino acid substitution may be E484K, as identified in certain South African and Brazilian variants; E484Q, as identified in certain Indian variants; and N501Y, as identified in certain British, Brazilian or South African variants; wherein said amino acid positions are defined with respect to the amino acid sequence SEQ ID NO: 1.
  • the peptide comprises an amino acid sequence
  • KGFNSYFPLQSYGCQPTNGVGYQCYR (with E484K substitution; SEQ ID NO: 7), QGFNSYFPLQSYGCQPTNGVGYQCYR (with E484Q substitution; SEQ ID NO: 8), EGFNSYFPLQSYGCQPTYGVGYQCYR (with N501Y substitution; SEQ ID NO: 9), or KGFNSYFPLQSYGCQPTYGVGYQCYR (with E484K and N501Y substitutions; SEQ ID NO: 10), wherein said amino acid positions are defined with respect to the amino acid sequence SEQ ID NO: 1.
  • the peptide comprises an amino acid sequence
  • the peptide comprises an amino acid sequence selected in the group comprising or consisting of SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 7,
  • cysteines C497 and C507 of sequence SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11 are covalently linked, wherein said amino acid positions are defined with respect to the amino acid sequence SEQ ID NO: 1.
  • cysteines C497 and C507 of sequence SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11 are covalently linked by a disulfide bridge or by an alkyl group.
  • cysteines C497 and C507 of sequence SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11 are covalently linked by a disulfide bridge, wherein said amino acid positions are defined with respect to the amino acid sequence SEQ ID NO: 1.
  • the covalent link is a disulfide bond.
  • the disulfide bridge may be the result of the covalent interaction of 2 -SH groups from 2 cysteine residues, so as to form a -S-S- disulfide bond.
  • cysteines C497 and C507 of sequence SEQ ID NO: 3,SEQ ID NO: 4, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11 are covalently linked by an alkyl group, wherein said amino acid positions are defined with respect to the amino acid sequence SEQ ID NO: 1.
  • cysteines C497 and C507 of sequence SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11 are alkylated, preferentially by an alkylating agent selected in a group comprising or consisting of a,a’-bisbromoxylene, hexafluorobenzene, 2,2'-bis(bromomethyl)-l,l'-biphenyl, 1,2- bis(bromom ethyl) benzene, 1,4-bis (bromomethyl)benzene, 3,3'-bis(bromomethyl)-l,l'- biphenyl and 4,4'-bis (bromomethyl)-l,l'-biphenyl.
  • the covalent bond may be the result of the covalent interaction of the alkyl group with the 2 -SH groups from 2 cysteine residues, so as to form a -S
  • the peptides according to the invention may be synthesized following suitable of method known from the state of the art, or a method adapted therefrom, including recombinant technologies or chemical synthesis.
  • recombinant technologies allow to synthesize linear peptides or cyclic peptides according to the invention, following the protocols available in the state in the art, or protocols adapted therefrom.
  • Non-limitative steps for recombinant technologies include the cloning of a nucleic acid encoding the peptide according to the invention in a suitable vector, in particular a bacterial vector or a viral vector; introducing the vector in a cell, in particular a bacterium (such as, e.g ., E. coli) by transformation (such as, e.g.
  • the peptide is an isolated peptide.
  • the peptide is a synthetic peptide.
  • chemical synthesis may be performed as solid-phase peptide synthesis (SPPS), in particular onto an appropriate solid support.
  • the solid-phase peptide synthesis (SPPS) may include the use of one or more protecting group(s), in particular selected in the group consisting of tert-butyloxycarbonyl (also referred to as “Boc” or “tBu”), fluorenylmethyloxycarbonyl (also referred to as “Fmoc”), carboxybenzyl, allyloxycarbonyl (also referred to as “Alloc”), and the like.
  • the synthesized peptide according to the invention is linear.
  • a “linear peptide” is intended to refer to a peptide that is not cyclic, i.e. a peptide in which the -SH groups of the 2 cysteines residues (namely cysteines C497 and C507) are not engaged in a covalent link, such as, e.g ., a disulfide bridge.
  • cyclic peptides according to the invention may be obtained by cyclization of linear peptides.
  • cyclization of linear peptides so as to allow disulfide bridge formation from free intrachain -SH groups may be performed according to any suitable method known from the state of the art, or a method adapted therefrom.
  • linear peptide may be incubated in an acidic solution, preferably a solution with a pH lower to about 6.0, in particular a pH of at most about 5.0.
  • the acidic solution comprising the linear peptide may be brought progressively to a neutral pH, in particular a pH comprised from about 6.5 to about 7.5.
  • the term “cyclization”, “refolding” or “renaturation” may substitute to one another.
  • the peptide is an immunogenic peptide.
  • the peptides according to the instant invention are epitopes of the S-protein from the SARS- CoV-2 virus, they are capable of eliciting an immune response upon contact with an individual.
  • one or more amino acid residues from the peptide comprising an amino acid sequence of SEQ ID NO: 3 or SEQ ID NO: 4 may be substituted for amino acid residues belonging to the same category, so as to maintain similar structure and/or function.
  • small neutral amino acid residues such as glycine (G), alanine (A), leucine (L), valine (V) or isoleucine (I) may substitute one another.
  • Negatively charged amino acid residues such as aspartic acid (D) and glutamic acid (E) may substitute one another.
  • Positively charges amino acid residues, such as histidine (H), lysine (K) and arginine (R) may substitute one another.
  • Aromatic amino acid residues such as tryptophan (W), tyrosine (Y) and phenylalanine (F) may substitute one another.
  • Serine (S) and threonine (T) may substitute one another.
  • Asparagine (N) and glutamine (Q) may substitute one another.
  • glutamate (Q) may be substituted with tyrosine (Y), histidine (H), phenylalanine (F), threonine (T), arginine (R), proline (P) or alanine (A).
  • glutamic acid (E) may be substituted with proline (P) or threonine (T).
  • phenylalanine (F) may be substituted with leucine (L), lysine (K), or proline (P).
  • serine (S) may be substituted with aspartic acid (D), arginine (R), or glycine (G).
  • proline (P) may be substituted with threonine (T), isoleucine (I), or glutamate (Q).
  • asparagine (N) may be substituted with threonine (T), aspartic acid (D), or serine (S).
  • tyrosine (Y) may be substituted with histidine (H).
  • amino acid residue(s) substitution(s) in any one of the peptides according to the invention may be naturally occurring substitution(s).
  • the two cysteine residues of the peptide are invariable. In one embodiment, the peptide does not comprise any further cysteine residue.
  • the structural and/or functional variant of the peptide comprising an amino acid sequence of SEQ ID NO: 4 comprises one or more amino acid substitutions selected in the group consisting of Q498R, Q498N, Q498Y, Q498H, Q498F or Q498T; P499T, P499I or P499Q; T500I or T500S; N501Y, N501Q, N501D, N501S or N501T; G502A; V503A, V503L or V503I; G504A; Y505F, Y505W or Y505H; Q506N, Q506H or Q506P, wherein said amino acid positions are defined with respect to the amino acid sequence SEQ ID NO: 1.
  • the peptide according to the invention, the structural variant thereof, or the functional variant thereof that binds to the ACE2 receptor comprises an amino acid sequence represented the following formula (I):
  • - X 1 is Q, R, N, Y, H, F, T;
  • - X 4 is N, Y, Q, D, S, T; - X 5 is V, I, A, L;
  • - X 6 is Y, F, W, H.
  • X 4 is N (N501). In certain embodiments, X 4 is Y (Y501).
  • the amino acid of formula (I) is such that Xi is Q (Q498), X 3 is T (T500), X 4 is N (N501) and X 6 is Y (Y505). In some embodiments, the amino acid of formula (I) is such that X 1 is Q (Q498), X 3 is T (T500), X 4 is Y (Y501) and X 6 is Y (Y505).
  • the structural and/or functional variant of the peptide comprising an amino acid sequence of SEQ ID NO: 3 comprises one or more amino acid substitutions selected in the group consisting of E848K, E484Q, E484D, E484P or E484T; G485A, G485R or G485V; F486Y, F486W, F486L or F486P; N487Q; S488T;
  • the peptide according to the invention, the structural variant thereof, or the functional variant thereof that binds to the ACE2 receptor comprises an amino acid sequence represented the following formula (II):
  • - X 2 is G, A, R, V; - X 3 is F, Y, W, L, P;
  • - X 5 is F, Y, W, K;
  • - X 6 is Q, N, Y, R, L, A;
  • - X7 is S, T, P, D, R, G; - X 8 is Q, N, Y, H, F, R, T;
  • - X 11 is N, Y, Q, D, S, T;
  • - X 12 is V, I, A, L; - X 13 is Y, F, W, H.
  • the amino acid of formula (II) is such that X 1 is E (E484) or K (K484) or Q (Q484), and/or X 3 is F (F486), and/or X 6 is Q (Q493), and/or X 11 is N (N501) or Y (Y501). In certain embodiments, the amino acid of formula (II) is such that Xi is K (K484) or Q (Q484), and/or X 11 is Y (Y501).
  • the amino acid of formula (II) is such that X 1 is E (E484) or K (K484) or Q (Q484), and/or X 3 is F (F486), and/or X6 is Q (Q493), and/or X 8 is Q (Q498), and/or X 10 is T (T500), and/or X 11 is N (N501) or Y (Y501), and/or X 13 is Y (Y505).
  • the amino acid sequence consists of SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11. In one embodiment, the amino acid sequence consists of SEQ ID NO: 3. In one embodiment, the amino acid sequence consists of SEQ ID NO: 4.
  • the peptide consists of amino acid sequence of SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11. In one embodiment, the peptide consists of an amino acid sequence of SEQ ID NO: 3. In one embodiment, the peptide consists of an amino acid sequence of
  • the immunogenicity of the peptide according to the instant invention may be enhanced in the presence of a carrier protein.
  • the peptide is conjugated to a carrier protein, preferably selected in the group consisting of adenylate cyclase toxin (ACT), bovine serum albumin (BSA), cholera toxin B subunit, CRM197, diphtheria toxoid, limpet hemocyanin (KLH), ovalbumin, pneumolysin, purified protein derivative of tuberculin (PPD), tetanus toxoid, and the like.
  • ACT adenylate cyclase toxin
  • BSA bovine serum albumin
  • cholera toxin B subunit CRM197
  • diphtheria toxoid diphtheria toxoid
  • KLH limpet hemocyanin
  • ovalbumin ovalbumin
  • pneumolysin purified protein derivative of tuberculin (PPD), tetanus toxoid, and the like.
  • the peptide and the carrier protein are conjugated by the mean of a linker.
  • linker is meant to refer to a single covalent bond or a stretch comprising series of stable covalent bonds, the stretch often incorporating from about 1 to about 500 plural valent atoms selected from the group consisting of C, N, O, S and P, that covalently attach a coupling function or a bioactive group to the peptide and/or the carrier protein according to the invention.
  • the number of plural valent atoms in a linker may be, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 25, 30, 40, 50, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490 or 500.
  • a linker may be linear, branched or ramified; and some linkers may have pendant side chains, or pendant functional groups, or a combination thereof.
  • Another aspect of the invention pertains to a nucleic acid encoding a peptide according to the instant invention.
  • nucleic acid a peptide according to the instant invention may be comprised in a nucleic acid vector, in particular a nucleic acid expression vector.
  • suitable nucleic acid expression vectors include chromosomes, plasmids, cosmids, bacterial artificial chromosomes (BAC), viral vectors, and the like.
  • chromosome refers to a genomic DNA nucleic acid molecule, originating from a micro-organism or a eukaryote.
  • plasmid refers to a small extra-genomic DNA nucleic acid molecule, most commonly found as circular double stranded DNA nucleic acid molecules that may be used as a cloning and/or expression vector.
  • the term “cosmid” refers to a hybrid plasmid that contains cos sequences from Lambda phage, allowing packaging of the cosmid into a phage head and subsequent infection of bacterial cell wherein the cosmid is cyclized and can replicate as a plasmid.
  • bacterial artificial chromosome or “BAC” refers to an extra-genomic nucleic acid molecule based on a functional fertility plasmid that allows the even partition of said extra-genomic DNA molecules after division of the bacterial cell.
  • viral vector refers to a nucleic acid vector originating in part from a virus and prone to infect eukaryote cells.
  • suitable viral vectors include, but are not limited to, adenoviral, retroviral, herpes virus and AAV vectors.
  • recombinant viral vectors may be produced by techniques known in the art, such as by transfecting packaging cells or by transient transfection with helper plasmids or viruses.
  • the invention relates to a composition
  • a composition comprising (i) a peptide according to the instant invention and (ii) an acceptable vehicle.
  • the composition is a pharmaceutical composition.
  • the pharmaceutical composition comprises a pharmaceutically acceptable vehicle.
  • pharmaceutically acceptable vehicle refers to any solvent, dispersion medium, coating, antibacterial and/or antifungal agent, isotonic and absorption delaying agent and the like.
  • the pharmaceutically acceptable vehicle may comprise one or more ingredient(s) selected in a group of additives polypeptides; amino acids; lipids; and carbohydrates.
  • sugars including monosaccharides, di-, tri-, tetra-, and oligosaccharides; derivatized sugars such as alditols, aldonic acids, esterified sugars and the like; and polysaccharides or sugar polymers.
  • Non-limitative example of polypeptidic pharmaceutically acceptable vehicle may include gelatin, casein, and the like.
  • the composition is an immunogenic composition.
  • compositions in particular a vaccine composition, comprising (i) a peptide as described herein and (ii) an acceptable vehicle.
  • the composition is a vaccine composition.
  • the vaccine composition comprises an adjuvant, in particular selected in the group consisting of alum, carbohydrate-based adjuvant, cholera toxin, CpG, Freund’s adjuvant, liposomes, monophoshoryl lipid A, oil-in-water (O/W) emulsion, saponin, water-in-oil (W/O) emulsion, a toll-like receptor, the like, and combination thereof.
  • the carbohydrate-based adjuvant is selected in the group comprising delta inulin, dextran, lentinan, zymosan, beta-glucan, mannan, chitin, muramylpeptide, cord factor, lipopolysaccharide (LPS), QS21.
  • carbohydrate-based adjuvants are also described by Petrovsky and Cooper (Expert Rev Vaccines. 2011 Apr; 10(4): 523-537) and Petrovsky (Novel Technologies for Vaccine Development; Chapter 7; I.S. Lukashevich, H. Shirwan (eds.); Springer-Verlag Wien 2014), which are incorporated by reference herein.
  • Toll-like receptors are intended to refer to the receptors that are commonly expressed in various cell types, especially antigen-presenting cells (APCs), including dendritic cells (DCs), B lymphocytes, and macrophages.
  • APCs antigen-presenting cells
  • DCs dendritic cells
  • B lymphocytes B lymphocytes
  • macrophages TLR ligand-based adjuvants are used in vaccines to stimulate these immune cells, to induce, and to boost protective immune responses, linking the innate and adaptive immunity.
  • the toll-like receptor is selected in the group consisting of TLR2, TLR3, TLR4, TLR5, TLR6, TLR9, and the like.
  • the vaccine composition is adjuvant-free.
  • the composition is lyophilized.
  • freeze-drying may be performed accordingly any one of the protocols disclosed in the state of the art, or a protocol adapted therefrom.
  • the freeze-drying of the composition is performed at a temperature of about -80°C, under vacuum.
  • One aspect of the invention relates to the use of a peptide as described herein for the manufacture of a composition for preventing and/or treating an infection by a virus of the SARS-CoV-2 coronavirus family.
  • the invention also relates to the use of a peptide or a composition as described herein for preventing and/or treating an infection by a virus of the SARS-CoV-2 coronavirus family.
  • Another aspect of the invention relates to a peptide as described herein for use for the preparation or the manufacture of a medicament or a composition for preventing and/or treating an infection by a virus of the SARS-CoV-2 coronavirus family.
  • Another aspect of the invention relates to a peptide or a composition as described herein for use for preventing and/or treating an infection by a virus of the SARS-CoV-2 coronavirus family.
  • Another aspect of the invention pertains to a method of preventing and/or treating an infection of an individual with a virus of the SARS-CoV-2 coronavirus family, comprising administering to the individual a therapeutic effective amount of a peptide or a composition as described herein.
  • composition may be a pharmaceutical composition, an immunogenic composition, a vaccine composition.
  • the term “treating an infection by a virus of the SARS-CoV-2 coronavirus family”, encompasses reducing or alleviating at least one symptom of the infection, in particular fever, cough, shortness of breath, fatigue, myalgia, gastrointestinal symptoms, chemosensory dysfunction (such as, e.g. , anosmia and dysgeusia), viral encephalitis, myocarditis and cutaneous lesions (such as, e.g., erythematous rash, widespread urticaria).
  • the monitoring of the symptoms may be performed according the general practice acknowledged in the state of the art, in particular by physical examination by authorized personnel.
  • fever may be monitored by the corporeal temperature, in particular by the mean of a thermometer; fatigue, myalgia, chemosensory dysfunction may be monitored by a medical survey. Shortness of breath may be monitored by a medical survey and/or a chest X-ray, an oxygen test, an electrocardiography. Viral encephalitis may be monitored by physical examination, blood tests, laboratory examination of cerebrospinal fluid, computed tomography (CT) scan, electroencephalography (EEG) or magnetic resonance imaging (MRI). Myocarditis may be monitored by an electrocardiogram (ECG), blood test, heart MRI, and heart biopsy. Cutaneous lesions may be monitored by a dermatologist.
  • CT computed tomography
  • EEG electroencephalography
  • MRI magnetic resonance imaging
  • ECG electrocardiogram
  • Cutaneous lesions may be monitored by a dermatologist.
  • the viral load refers to the number of viral particles found in each milliliter. In practice, the viral load is or may be measured according to the standard procedures in the field, or adapted procedures therefrom.
  • the term “preventing an infection by a virus of the SARS-CoV-2 coronavirus family” encompasses the prevention of the occurrence of any one of the symptoms of the infection, and/or the prevention of a detectable viral load.
  • the peptide or the composition according to the instant invention may be or is to be combined with one or more additional treatment(s), including one or more active ingredient(s), so as to combat the SARS-CoV-2 virus itself or the symptoms associated with an infection with the SARS-CoV-2 virus.
  • Non-limitative examples of additional treatment(s), including active ingredients, of interest include anti-inflammatory compounds, such as, e.g ., corticosteroids; antibiotics, in particular antibiotics against lung infections; antiviral compounds; antifungal compounds; and the like.
  • said additional treatment s), including active ingredients may be or is to be administered before, concomitantly or after the administration of the peptide or the composition according to the instant invention.
  • the invention further relates to the use of a peptide or a composition as described herein for eliciting an immune response against a virus of the SARS-CoV-2 coronavirus family.
  • One aspect of the invention pertains to a peptide or a composition as described herein for use for eliciting an immune response against a virus of the SARS-CoV-2 coronavirus family.
  • the invention further relates to a method for eliciting an immune response against a virus of the SARS-CoV-2 coronavirus family in an individual in need thereof, comprising administering to the individual a therapeutic effective amount of a peptide or a composition as described herein.
  • the immune response comprises the production of B lymphocytes capable of synthesizing antigen-specific antibodies, and/or the production of macrophages, and/or the production of killer T lymphocytes that are specific of the antigen and/or the production of cytokines, including pro-inflammatory cytokines (such as, e.g. , IL-Ib, TNFa and IL-6), chemokine, Thl type cytokines (such as, e.g. , IL-12, TNF ⁇ and IFN- g), and Th2 type cytokines (such as, e.g, IL-4, IL-5, IL-9 and IL-13).
  • pro-inflammatory cytokines such as, e.g. , IL-Ib, TNFa and IL-6
  • chemokine such as, e.g. , IL-12, TNF ⁇ and IFN- g
  • Th2 type cytokines such as, e.g, IL-4, IL-5, IL
  • assessing the immune response in an individual is performed by any suitable method available from the state of the art or a method adapted therefrom.
  • assessing the immune response in an individual may be performed by measuring the level of antigen-specific antibodies in a blood sample collected from the individual, in particular a plasma or a serum; by measuring the level of macrophages and/or of antigen-specific killer T lymphocytes in a blood sample or a biopsy collected from the individual; by measuring the level of circulating cytokines in a blood sample collected from the individual.
  • the immune response against a virus of the SARS-CoV-2 coronavirus family comprises or essentially consists of the production of neutralizing antibodies.
  • neutralizing antibody refers to an antibody that binds to the virus itself, and therefore interferes with its ability to infect a targeting cell.
  • the invention relates to the use of a peptide or a composition as described herein for vaccinating an individual against a SARS-CoV-2 infection.
  • One aspect of the invention relates to a peptide or a composition as described herein for use for vaccinating an individual against a SARS-CoV-2 infection.
  • One aspect of the invention pertains to a method of vaccinating an individual in need thereof against a SARS-CoV-2 infection, comprising administering to the individual an effective amount of a peptide or a composition as described herein.
  • the vaccine composition according to the instant invention may be or is to be combined with one or more additional vaccine composition(s).
  • Non-limitative examples of additional vaccine compositions of interest include vaccine compositions against other viral infection, such as, e.g. , the Influenza virus.
  • said additional vaccine composition may be or is to be administered before, concomitantly or after the administration of vaccine composition according to the instant invention.
  • the invention relates to the use of a peptide or a composition as described herein for inhibiting the interaction between a SARS-CoV-2 spike protein (S-protein) with an ACE2 receptor.
  • One aspect of the invention relates to a peptide or a composition as described herein for use for inhibiting the interaction between a SARS- CoV-2 spike protein (S-protein) with an ACE2 receptor.
  • Another aspect of the invention relates to a method for inhibiting the interaction between a SARS-CoV-2 spike protein (S-protein) with an ACE2 receptor in an individual in need thereof, comprising administering to the individual an effective amount of a peptide or a composition as described herein.
  • S-protein SARS-CoV-2 spike protein
  • the term “inhibiting the interaction between a SARS- CoV-2 spike protein (S-protein) with an ACE2 receptor” refers to a level of binding of SARS-CoV-2 spike protein to an ACE2 receptor reaching at most about 75% of the level of binding observed in vivo or in vitro under standard conditions, as disclosed in the state of the art.
  • the expression “at most about 75%” encompasses about 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, 1%, 0.5%, 0.1%, 0.05%, 0.01%, 0.005% and 0.001%.
  • assessing the binding of the SARS-CoV-2 spike protein to an ACE2 receptor may be evaluated in vitro , according to any suitable method known from the state in the art, or a method adapted therefrom.
  • the levels binding of the SARS-CoV-2 spike protein (S-protein) to an ACE2 receptor may be qualitatively and/or quantitatively measured by Biacore; Isothermal titration calorimetry (ITC); native electrochromatography; co-separation-based techniques, such as for example co- immunoprecipitation, GST pull-down and the like; fluorescence-based assays, such as for example FRET, BiFC and the like; surface plasmon resonance-based assay; genetic reporter-based assays such as for example, yeast-2-hybrid, phage display and the like.
  • the individual is at risk of being infected by virus of the SARS- CoV-2 coronavirus family.
  • the individual at risk of being infected by virus of the SARS- CoV-2 coronavirus family is an individual susceptible to undergo severe medical condition, in particular life-threatening medical condition.
  • the individual is above 60 years old, in particular above 65 years old, more particularly above 70 years old.
  • the individual is overweight or obese.
  • the individual is with a cardiac disease.
  • the individual is with a chronic respiratory disease.
  • the individual is with cancer, in particular is further undergoing a cancer treatment.
  • the individual is with a chronic kidney disease, in particular is in need of dialysis. In some embodiments, the individual is with immunodepression. In some embodiments, the individual is with a liver disease, in particular with a chronic liver disease. In some embodiments, the individual is a pregnant female individual.
  • the individual is human.
  • the peptide or the composition is to be administered orally, parenterally, subcutaneously, intramuscularly, intradermally, intramucosally, intravenously or intranasally, preferably intradermally.
  • the peptide or the composition is to be administered intradermally.
  • intradermal administration results in the immunogenic peptide according to the invention to be less the subject of protease degradation, as compared to intramuscular or sub-cutaneous administration. Consequently, intradermal administration improves the half-life of the immunogenic peptide according to the invention.
  • the treatment may consist of administering to the individual at least a single dose, or alternatively a plurality of doses over a period of time.
  • the effective amount of the peptide to be administered may depend upon a variety of parameters, including the material selected for administration, whether the administration is in single or multiple doses, and the subject’s parameters including age, physical conditions, size, weight, gender, and the severity of the infection to be treated.
  • an effective amount of the peptide according to the invention may comprise from about 0.001 mg to about 3,000 mg, per dosage unit, preferably from about 0.05 mg to about 1,000 mg, per dosage unit.
  • from about 0.001 mg to about 3,000 mg includes, about 0.001 mg, 0.002 mg, 0.003 mg, 0.004 mg, 0.005 mg, 0.006 mg, 0.007 mg, 0.008 mg, 0.009 mg, 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1,000
  • Another aspect of the invention pertains to a method for the screening of compound that bind to the peptide as disclosed herein, comprising: a) contacting the peptide according to the instant invention with a candidate compound; b) detecting a binding of the peptide to the candidate compound.
  • step a) is performed in conditions suitable for an interaction to occur, in particular suitable salinity, suitable pH, suitable temperature, suitable duration. In practice, these parameters can easily be determined by routine procedures.
  • the candidate compound is an aptamer.
  • the term “aptamer” refers to an oligonucleotide or peptide molecule that bind to a specific target molecule. In practice, the aptamer is selected in the group consisting of small organic molecules, nucleic acids, peptides, polypeptides, cells. In one embodiment, the aptamer is not an antibody or a fragment thereof.
  • the compound is an antibody or a fragment thereof, in particular a neutralizing antibody or a fragment thereof.
  • neutralizing antibody refers to an antibody that binds to the virus itself, and therefore interferes with its ability to infect a targeting cell.
  • One aspect of the invention relates to a method for the screening of an antibody or a fragment thereof that binds to the peptide as disclosed herein, comprising: a) contacting the peptide according to the instant invention with a candidate antibody or fragment thereof; b) detecting a binding of the peptide to the candidate antibody or fragment thereof.
  • step a) is performed in conditions allowing binding of the candidate compound, or the candidate antibody or fragment thereof, to bind to the peptide according to the instant invention.
  • Said conditions may depend from the salinity, pH, temperature in which the assay is performed. These parameters may be easily adjusted by routine procedures well known in the state of the art.
  • an “antibody”, also referred to as immunoglobulins (abbreviated “Ig”), is intended to refer to a gamma globulin protein that is found in blood or other bodily fluids of vertebrates, and is used by the immune system to identify and neutralize foreign objects, such as bacteria and viruses.
  • Antibodies consist of two pairs of polypeptide chains, called heavy chains and light chains that are arranged in a Y-shape. The two tips of the Y are the regions that bind to antigens and deactivate them.
  • antibody as used herein includes monoclonal antibodies, polyclonal antibodies, multi-specific antibodies (e.g ., bispecific antibodies), and antibody fragments, so long as they exhibit the desired biological activity.
  • immunoglobulin Ig is used interchangeably with “antibody” herein.
  • an “antibody fragment” comprises a portion of an intact antibody, preferably the antigen binding or variable region of the intact antibody.
  • antibody fragments include Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies (see U.S. Pat. No. 5,641,870; Zapata et al. , Protein Eng. 8(10): 1057-1062 (1995)); single-chain antibody molecules; and multi-specific antibodies formed from antibody fragments.
  • One may refer to a “functional fragment or analog” of an antibody, which is a compound having qualitative biological activity in common with a full- length antibody.
  • a functional fragment or analog of an anti-IgE antibody is one that can bind to an IgE immunoglobulin in such a manner so as to prevent or substantially reduce the ability of such molecule from having the ability to bind to the high affinity receptor, Fc[epsilon]RI.
  • Papain digestion of antibodies produces two identical antigen-binding fragments, called “Fab” fragments, and a residual “Fc” fragment, a designation reflecting the ability to crystallize readily.
  • the Fab fragment consists of an entire L chain along with the variable region domain of the H chain (VET), and the first constant domain of one heavy chain (CHI). Each Fab fragment is monovalent with respect to antigen binding, i.e., it has a single antigen-binding site.
  • F(ab')2 antibody fragments differ from Fab fragments by having additional few residues at the carboxy terminus of the CHI domain including one or more cysteines from the antibody hinge region.
  • Fab'-SH is the designation herein for Fab' in which the cysteine residue(s) of the constant domains bear a free thiol group.
  • F(ab')2 antibody fragments originally were produced as pairs of Fab' fragments that have hinge cysteines between them. Other chemical couplings of antibody fragments are also known.
  • antibody/ies encompasses monoclonal antibody/ies, polyclonal antibody/ies, afucosylated antibody/ies, diabody/ies, triabody/ies, tetrabody/ies, nanobody/ies, and analog(s) thereof.
  • an “afucosylated antibody” refers to an antibody lacking core fucosylation. As a matter of fact, nearly all IgG-type antibodies are N-glycosylated in their Fc moiety. Typically, a fucose residue is attached to the first N-acetylglucosamine of these complex-type N-glycans. In other words, an “afucosylated antibody” refers to an antibody that does not possess N-glycans.
  • the term “diabody” refers to a small antibody fragment prepared by constructing sFv fragments (see preceding paragraph) with short linkers (about 5-10 residues) between the VH and VL domains such that inter-chain but not intra-chain pairing of the V domains is achieved, resulting in a bivalent fragment, /. e. , fragment having two antigen-binding sites.
  • Bispecific diabodies are heterodimers of two “crossover” sFv fragments in which the VH and VL domains of the two antibodies are present on different polypeptide chains.
  • Diabodies are described in more details in, e.g ., EP 404,097; WO 93/11161; and Hollinger et al. (Proc. Natl. Acad. Sci. USA, 90:6444- 6448 (1993)).
  • a “triabody” is intended to refer to an antibody that has three Fv heads, each consisting of a VH domain from one polypeptide paired with the VL domain from a neighboring polypeptide.
  • a “nanobody” refers to a functional antibody that consists of heavy chains only and therefore lack light chains. These heavy-chain only antibodies contain a single variable domain (VHH) and two constant domains (CH2, CH3).
  • VHH variable domain
  • CH3 constant domain
  • the antibody or the fragment thereof is a neutralizing antibody or a fragment thereof.
  • the antibody or the fragment thereof inhibits the interaction between a SARS-CoV-2 spike protein (S-protein) with an ACE2 receptor.
  • S-protein SARS-CoV-2 spike protein
  • the ACE2 receptor is a mammalian ACE2 receptor, preferably a human ACE2 receptor.
  • Another aspect of the invention pertains to a method for diagnosing an individual, preferably a human, infected by a virus of the SARS-CoV-2 coronavirus family, comprising: a) proving a blood sample, in particular a plasma or a serum, from the individual; b) contacting the blood sample with the peptide according to the invention; and c) assaying for the presence, in the blood sample, of antibodies that bind to the peptide; wherein the presence, in the blood sample, of antibodies that bind to the peptide is indicative of the individual being infected by the virus.
  • the individual is human.
  • the antibodies are selected in the group consisting of IgGs, IgAs, IgMs, the like, and a combination thereof.
  • step c) is performed by the mean of an ELISA technique or an immunochromatography technique.
  • the blood sample is whole blood, plasma or serum.
  • kits for preventing and/or treating an infection by a virus of the SARS-CoV-2 coronavirus family comprising: a) a peptide or a composition according to the instant invention; and b) means to administer the peptide or the composition.
  • the means to administer the peptide or the composition include a syringe.
  • Another aspect of the invention relates to a kit for diagnosing an infection by a virus of the SARS-CoV-2 coronavirus family, comprising: a) a peptide according to the instant invention; and b) means to assay an interaction between the peptide and a compound that binds to the peptide.
  • the kit when the peptide according to the instant invention is lyophilized, may comprise a solution or a suspension to rehydrate the peptide.
  • the means to assay an interaction between the peptide and a compound that binds to the peptide comprise one or more reactant(s) to perform ELISA or immunochromatography .
  • the compound that binds to the peptide is an antibody.
  • the antibody is selected in the group consisting of IgGs, IgAs and IgMs.
  • SEQ ID NO: 1 ( ⁇ R 009724390.1 surface glycoprotein tS-protein) [Severe acute respiratory syndrome coronavirus 21) MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDL FLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTT LDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSS ANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDL PQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQ PRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESI VRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSA
  • SEQ ID NO: 3 (peptide according to the invention) EGFNSYFPLQSYGCQPTNGVGYQCYR
  • Example 1 Synthesis of MimoCov2, a peptide of sequence SEQ ID NO: 3
  • the peptide synthesis was carried out with Fmoc/tBu chemistry using protecting group Trt for Cys (C), Asn (N) and Gin (Q), tBu for Glu, Ser (S), Thr (T) and Tyr (Y).
  • Amino acid residues were coupled with HCTU and NMM with a ratio A/HCTU/NMM (5eq/5eq/10eq).
  • TFA trifluoroacetic acid
  • Example 2 Local and systemic toxicity study of MimoCov2 (SEQ ID NO: 3) by the subcutaneous route in CD-I mice 1. Materials and methods
  • CD-I mice were treated as shown in Table 2 below.
  • Test item MimoCov2 peptide (SEQ ID NO: 3).
  • No hematoma 0; Hematoma of an area ⁇ 1 cm 2 : 1; Hematoma of an area > 1 cm 2 and ⁇ 2 cm 2 : 2; Hematoma of an area > 2 cm 2 and ⁇ 3 cm 2 : 3; Hematoma of an area > 3 cm 2 :
  • Activated partial thromboplastin time basophils; eosinophils; fibrinogen concentration; haematocrit; haemoglobin distribution width; haemoglobin; large unstained cells; lymphocytes; mean corpuscular haemoglobin; mean corpuscular haemoglobin concentration; mean corpuscular volume; monocytes; mean platelet volume; neutrophils; platelet crit ; platelet distribution width; platelets; prothrombin time; red blood cells; red blood cell distribution width; reticulocytes; thrombin time; vacuolated lymphocytes; white blood cells; were assessed accordingly to the standard protocols in the field. 1.4. Clinical chemistry
  • Albumin/globulin ratio albumin; alkaline phosphatase; alanine aminotransferase; amylase; aspartate aminotransferase; BB complement factor; blood glucose reading; bile acids; C3a complement factor; C3c complement factor; calcium; cholesterol; creatine kinase or creatine phosphokinase; chloride; creatinine; c-reactive protein; c- reactive protein high sensitivity; direct bilirubin; iron; gamma glutamyl-transferase; globulin; glutamate dehydrogenase; glucose; haptoglobin; high density lipoprotein; indirect bilirubin; potassium; lactate dehydrogenase; low density lipoprotein; magnesium; sodium; phosphorus; phospholipids; total bilirubin; total protein; triglycerides; urea nitrogen; were assessed accordingly to the standard protocols in the field.
  • the immunogenicity evaluation confirmed the exposure of treated mice to MimoCov2 as sustained specific IgG ELISA against MimoCov2 were induced.

Abstract

La présente invention concerne un peptide comprenant une séquence d'acides aminés ayant au moins environ 75 % d'identité de séquence à SEQ ID NO : 3 ou SEQ ID NO : 4, un variant structural de celui-ci, ou un variant fonctionnel de celui-ci qui se lie au récepteur ACE2, dans lequel les cystéines C497 et C507 de séquence SEQ ID NO : 3 ou SEQ ID NO : 4 sont invariables, lesdites positions d'acides aminés étant définies par rapport à la séquence d'acides aminés SEQ ID NO : 1.
PCT/EP2021/063091 2020-05-18 2021-05-18 Peptides mimotopes de la protéine spike du virus sars-cov-2 WO2021233885A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023118871A1 (fr) * 2021-12-21 2023-06-29 Imperial College Innovations Limited Vecteurs lentiviraux pseudotypés
CN116987152A (zh) * 2023-09-27 2023-11-03 中国科学院微生物研究所 一种新冠病毒环肽抑制剂
WO2023226988A1 (fr) * 2022-05-25 2023-11-30 中山大学 Procédé permettant d'améliorer l'immunogénicité d'un variant du sars-cov-2 et utilisation associée

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113278054B (zh) * 2021-06-24 2023-03-24 安徽大学 一种结合新冠病毒rbd位点的环肽及其制备方法和用途

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0404097A2 (fr) 1989-06-22 1990-12-27 BEHRINGWERKE Aktiengesellschaft Récepteurs mono- et oligovalents, bispécifiques et oligospécifiques, ainsi que leur production et application
WO1993011161A1 (fr) 1991-11-25 1993-06-10 Enzon, Inc. Proteines multivalentes de fixation aux antigenes
US5641870A (en) 1995-04-20 1997-06-24 Genentech, Inc. Low pH hydrophobic interaction chromatography for antibody purification
WO2005028497A2 (fr) 2003-09-15 2005-03-31 The Brigham And Women's Hospital Inc. Peptides se liant a des recepteurs derives de proteines sars s
WO2006051091A1 (fr) * 2004-11-11 2006-05-18 Crucell Holland B.V. Compositions contre le coronavirus du sras et utilisations de ces compositions
US20100150923A1 (en) 2005-06-20 2010-06-17 Chinese Academy Of Medical Sciences, Institute Of Basic Medical Sciences Fusion proteins of recombinant sars coronavirus structural proteins, their production and uses

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0404097A2 (fr) 1989-06-22 1990-12-27 BEHRINGWERKE Aktiengesellschaft Récepteurs mono- et oligovalents, bispécifiques et oligospécifiques, ainsi que leur production et application
WO1993011161A1 (fr) 1991-11-25 1993-06-10 Enzon, Inc. Proteines multivalentes de fixation aux antigenes
US5641870A (en) 1995-04-20 1997-06-24 Genentech, Inc. Low pH hydrophobic interaction chromatography for antibody purification
WO2005028497A2 (fr) 2003-09-15 2005-03-31 The Brigham And Women's Hospital Inc. Peptides se liant a des recepteurs derives de proteines sars s
WO2006051091A1 (fr) * 2004-11-11 2006-05-18 Crucell Holland B.V. Compositions contre le coronavirus du sras et utilisations de ces compositions
US20100150923A1 (en) 2005-06-20 2010-06-17 Chinese Academy Of Medical Sciences, Institute Of Basic Medical Sciences Fusion proteins of recombinant sars coronavirus structural proteins, their production and uses

Non-Patent Citations (26)

* Cited by examiner, † Cited by third party
Title
"Computer Analysis of Sequence Data", 1994, HUMANA PRESS
"Sequence Analysis Primer", 1991, M. STOCKTON PRESS
ALTSCHUL ET AL., J. MOL. BIOL., vol. 215, 1990, pages 403 - 410
CARILLO ET AL., SIAM J. APPLIED MATH, vol. 48, 1988, pages 1073
DEVEREUX ET AL.: "Nucl. Acid. Res", vol. 2, 1984, GENETICS COMPUTER GROUP, UNIVERSITY OF WISCONSIN, pages: 387
ETHAN FAST ET AL: "Potential T-cell and B-cell Epitopes of 2019-nCoV", BIORXIV, 18 March 2020 (2020-03-18), XP055716967, Retrieved from the Internet <URL:https://www.biorxiv.org/content/10.1101/2020.02.19.955484v2.full.pdf> [retrieved on 20210908], DOI: 10.1101/2020.02.19.955484 *
GILCHUK PAVLO ET AL: "Discovering protective CD8 T cell epitopes-no single immunologic property predicts it!", CURRENT OPINION IN IMMUNOLOGY, ELSEVIER, OXFORD, GB, vol. 34, 6 February 2015 (2015-02-06), pages 43 - 51, XP029605146, ISSN: 0952-7915, DOI: 10.1016/J.COI.2015.01.013 *
GREANEY ET AL., CELL HOST & MICROBE, vol. 29, 2021, pages 44 - 57
GURUPRASAD, PROTEINS, vol. 1-8, 2021
HOLLINGER ET AL., PROC. NATL. ACAD. SCI. USA, vol. 90, 1993, pages 6444 - 6448
HU ET AL., J. COMB. CHEM., vol. 7, 2005, pages 648 - 656
LEUNG ET AL., EURO SURVEILL.;, vol. 26, no. 1, 2021, pages 2002106
LU ET AL., TRENDS MICROBIOL, vol. 23, no. 8, 2015, pages 468 - 78
MALONIS RYAN J. ET AL: "Peptide-Based Vaccines: Current Progress and Future Challenges", CHEMICAL REVIEWS, vol. 120, no. 6, 25 March 2020 (2020-03-25), US, pages 3210 - 3229, XP055817917, ISSN: 0009-2665, Retrieved from the Internet <URL:https://pubs.acs.org/doi/pdf/10.1021/acs.chemrev.9b00472> [retrieved on 20210908], DOI: 10.1021/acs.chemrev.9b00472 *
MILLETWHITTAKE, PNAS, vol. 111, no. 42, 2014, pages 15214 - 9
ORTEGA ET AL., EXCLIS J, vol. 19, 2020, pages 410 - 417
ORTEGA ET AL., EXCLIS J., vol. 19, 2020, pages 410 - 417
PETROVSKY: "Novel Technologies for Vaccine Developmen", 2014, SPRINGER-VERLAG
PETROVSKYCOOPER, EXPERT REV VACCINES, vol. 10, no. 4, April 2011 (2011-04-01), pages 523 - 537
VON HEINJE, G.: "Sequence Analysis in Molecular Biology", 1987, ACADEMIC PRESS
WALLS ET AL., CELL, vol. 180, 2020, pages 1 - 12
WANG ET AL., ACS INFECT. DIS., vol. 2, 2016, pages 361 - 376
WANG QIDI ET AL: "Immunodominant SARS Coronavirus Epitopes in Humans Elicited both Enhancing and Neutralizing Effects on Infection in Non-human Primates", ACS INFECTIOUS DISEASES, vol. 2, no. 5, 13 May 2016 (2016-05-13), US, pages 361 - 376, XP055814678, ISSN: 2373-8227, Retrieved from the Internet <URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075522/pdf/id6b00006.pdf> [retrieved on 20210908], DOI: 10.1021/acsinfecdis.6b00006 *
ZAPATA ET AL., PROTEIN ENG., vol. 8, no. 10, 1995, pages 1057 - 1062
ZHANG BAO-ZHONG ET AL: "Mapping the Immunodominance Landscape of SARS-CoV-2 Spike Protein for the Design of Vaccines against COVID-19", BIORXIV, 27 April 2020 (2020-04-27), pages 1 - 23, XP055814675, Retrieved from the Internet <URL:https://www.biorxiv.org/content/10.1101/2020.04.23.056853v2.full.pdf> [retrieved on 20210616], DOI: 10.1101/2020.04.23.056853 *
ZHANG ET AL., BIORXIV, 27 April 2020 (2020-04-27)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023118871A1 (fr) * 2021-12-21 2023-06-29 Imperial College Innovations Limited Vecteurs lentiviraux pseudotypés
WO2023226988A1 (fr) * 2022-05-25 2023-11-30 中山大学 Procédé permettant d'améliorer l'immunogénicité d'un variant du sars-cov-2 et utilisation associée
CN116987152A (zh) * 2023-09-27 2023-11-03 中国科学院微生物研究所 一种新冠病毒环肽抑制剂
CN116987152B (zh) * 2023-09-27 2024-01-02 中国科学院微生物研究所 一种结合沙贝冠状病毒s蛋白rbd结构域的环肽及其应用

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