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1. (WO2018164573) INHIBITEURS DE POLYPEPTIDES VIRAUX
Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

Claims

1. Use of an inhibitor or a nucleic acid molecule encoding said inhibitor for inhibiting the biological activity of a viral protein, preferably a viral protease having

deubiquitination activity,

wherein the inhibitor comprises a beta-grasp fold, wherein said fold comprises region 1 (amino acids 2- 14), region 2 (amino acids 42-49), and region 3 (amino acids 62-76) of the amino acid sequence set forth in SEQ ID NO: l,

wherein the inhibitor comprises one or more amino acid substitutions in said regions as compared to the amino acid sequence set forth in SEQ ID NO: l, and

wherein said substitutions include an amino acid substitution of A to F at the amino acid position corresponding to 46 of SEQ ID NO: 1 and/or an amino acid substitution of E to Y at the amino acid position corresponding to 64 of SEQ ID NO: 1.

2. The use according to claim 1,

a) wherein region 1 has an amino acid sequence corresponding to amino acids 2- 14 of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5; SEQ ID NO: 12, or

SEQ ID NO: 14;

b) wherein region 2 has an amino acid sequence corresponding to amino acids 42-49 of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, or SEQ ID NO: 13; and/or

c) wherein region 3 has an amino acid sequence corresponding to amino acids 62-78 of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 13, SEQ ID NO: 15;

preferably wherein the inhibitor comprises an amino acid sequence selected from SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15.

3. Use of an inhibitor or a nucleic acid molecule encoding said an inhibitor for inhibiting the biological activity of a viral protein, preferably a viral protease having deubiquitination activity,

wherein the inhibitor comprises a beta-grasp fold, wherein said fold comprises region 1 (amino acids 2- 14), region 2 (amino acids 42-49), and region 3 (amino acids 62-76) of the amino acid sequence set forth in SEQ ID NO: l,

wherein the inhibitor comprises one or more amino acid substitutions in said regions as compared to the amino acid sequence set forth in SEQ ID NO: l, and

wherein said substitution include an amino acid substitution of R to G at the amino acid position corresponding to 74 of SEQ ID NO: 1.

4. The use according to claim 3,

a) wherein region 1 has an amino acid sequence corresponding to amino acids 2- 14 of SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO: 10; b) wherein region 2 has an amino acid sequence corresponding to amino acids 42-49 of SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO: 10; and/or

c) wherein region 3 has an amino acid sequence corresponding to amino acids 62-78 of SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO: 10, preferably wherein the inhibitor comprises an amino acid sequence selected from SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO: 10.

5. The use according to any one of the preceding claims wherein the use is for inhibiting the proteolytic cleavage activity of a viral protein.

6. The use according to any one of the preceding claims, wherein region 1 is linked to region 2 by a polypeptide comprising amino acids 15-41 of SEQ ID NO: 1 or having at least 80% identity to amino acids 15-41 of SEQ ID NO: 1 and where in region 2 is linked to region 3 by a polypeptide comprising amino acids 50-61 of SEQ ID NO: 1 or having at least 80% identity to amino acids 50-61 of SEQ ID NO: 1.

7. An inhibitor comprising a beta-grasp fold, wherein said fold comprises region 1 (amino acids 2- 14), region 2 (amino acids 42-49), and region 3 (amino acids 62-76) of the amino acid sequence set forth in SEQ ID NO: l,

wherein the inhibitor comprises one or more amino acid substitutions in said regions as compared to the amino acid sequence set forth in SEQ ID NO: l, and

wherein said substitutions include an amino acid substitution of A to F at the amino acid position corresponding to 46 of SEQ ID NO: 1 and/or an amino acid substitution of E to Y at the amino acid position corresponding to 64 of SEQ ID NO: 1.

8. An inhibitor comprising a beta-grasp fold, wherein said fold comprises region 1 (amino acids 2- 14), region 2 (amino acids 42-49), and region 3 (amino acids 62-76) of the amino acid sequence set forth in SEQ ID NO: l,

wherein the inhibitor comprises one or more amino acid substitutions in said regions as compared to the amino acid sequence set forth in SEQ ID NO: l, and

wherein said substitution include an amino acid substitution of R to G at the amino acid position corresponding to 74 of SEQ ID NO: 1.

9. A nucleic acid molecule encoding the inhibitor of claims 7 or 8.

10. A recombinant expression vector expressing the nucleic acid molecule of claim 9.

11. An in vitro cell line, or a non-human cell or non-human organism comprising the inhibitor of claims 7 or 8, the nucleic acid molecule of claim 9, or the recombinant expression vector of claim 10.

12. A pharmaceutical composition comprising the inhibitor of claims 7 or 8, the nucleic acid molecule of claim 9, or the recombinant expression vector of claim 10.

13. An inhibitor or a nucleic acid molecule encoding said inhibitor for use in therapy, wherein the inhibitor comprises a beta-grasp fold, wherein said fold comprises region

1 (amino acids 2- 14), region 2 (amino acids 42-49), and region 3 (amino acids 62-76) of the amino acid sequence set forth in SEQ ID NO: l,

wherein the inhibitor comprises one or more amino acid substitutions in said regions as compared to the amino acid sequence set forth in SEQ ID NO: l, and

wherein said substitutions include an amino acid substitution of A to F at the amino acid position corresponding to 46 of SEQ ID NO: 1 and/or an amino acid substitution of E to Y at the amino acid position corresponding to 64 of SEQ ID NO: 1, preferably wherein the use is for the treatment and/or prevention of Middle East respiratory syndrome coronaviral (MERS-CoV) infection and/or the symptoms thereof.

14. An inhibitor or a nucleic acid molecule encoding said an inhibitor for use in therapy,

wherein the inhibitor comprising a beta-grasp fold, wherein said fold comprises region 1 (amino acids 2- 14), region 2 (amino acids 42-49), and region 3 (amino acids 62-76) of the amino acid sequence set forth in SEQ ID NO: l,

wherein the inhibitor comprises one or more amino acid substitutions, in said regions as compared to the amino acid sequence set forth in SEQ ID NO: l, and

wherein said substitution include an amino acid substitution of R to G at the amino acid position corresponding to 74 of SEQ ID NO: 1, preferably wherein the use is for the treatment and/or prevention of Crimean-Congo hemorrhagic fever viral infection and/or the symptoms thereof.

15. A method of identifying an inhibitor or a nucleic acid molecule encoding said inhibitor that inhibits the biological activity of a viral ubiquitin binding protein partner, the method comprising providing a library of polypeptides and screening said library against a viral ubiquitin binding partner in order to identify inhibitors that bind to said viral ubiquitin binding partner, wherein said polypeptide library comprises at least 1000 different polypeptides, wherein each polypeptide comprises a beta-grasp fold comprising region 1 (amino acids 2- 14), region 2 (amino acids 42-49), and region 3 (amino acids 62-76) of the amino acid sequence set forth in SEQ ID NO: l and comprises at least one amino acid mutation in said regions as compared to the amino acid sequence set forth in SEQ ID NO: l.