Stabilized antiviral fusion helices
AssigneeDana-Farber Cancer Institute, Inc.
InventorsLoren D. Walensky, Gregory H. Bird
Life of this patent
Estimating the term…
Abstract
Internally cross-linked peptides useful for interfering with Respiratory Syncytial Virus (RSV) infection is based on RSV-F protein. These peptides are capable of reducing infection in cellular and animal models.
Claims37
An internally cross-linked polypeptide comprising the amino acid sequence A0B0C0D0E0F0G0 A1B1C1D1E1F1G1A2B2C2D2E2F2G2A3B3C3D3E3F3G3A4B4C4D4E4F4G4 (SEQ ID NO:1) wherein:
- A0 is Phe;
- B0 is Asp or Glu;
- C0 is Ala, Val, Ile, Leu, or Ser;
- D0 is Ser;
- E0 is Ile;
- F0 is Ser or Thr;
- G0 is Gln or Asn;
- A1 is Val;
- B1 is Asn or Gln;
- C1 is Glu or Asp;
- D1 is Lys;
- E1 is Ile;
- F1 is Asn or Gln;
- G1 is Gln or Asn;
- A2 is Ser;
- B2 is Leu;
- C2 is Ala, Val, Leu, Ser, or Ile;
- D2 is Phe;
- E2 is Ile;
- F2 is Arg or Lys;
- G2 is Lys;
- A3 is Ser;
- B3 is Asp;
- C3 is Glu or Asp;
- D3 is Leu;
- E3 is Leu;
- F3 is His, Arg, or Lys;
- G3 is Asn or Gln;
- A4 is Val;
- B4 is Asn;
- C4 is Ala, Leu, Ile, Ser, or Val;
- D4 is Gly;
- E4 is Lys;
- F4 is Ser or Thr;
- and
- G4 is Thr or Ser;
- wherein
- zero to five amino acids at positions corresponding to A0, D0, E0, A1, D1, E1, A2, B2, D2, E2, A3, B3, D3, E3, A4, B4, D4, and E4 are substituted by a conservative amino acid;
- two to four amino acids of SEQ ID NO:1 separated by two, three, or six amino acids are replaced with non-natural amino acids with olefinic side chains, and:
- if two amino acids of SEQ ID NO:1 are replaced with non-natural amino acids, then the side chains of the two amino acids are joined by an internal staple;
- if three amino acids of SEQ ID NO:1 are replaced with non-natural amino acids, then the side chains of the three amino acids are joined by internal staples and/or an internal stitch;
- or
- if four amino acids of SEQ ID NO:1 are replaced with non-natural amino acids, then the side chains of the four amino acids are joined by internal staples, internal stiches, or a combination of internal staples and stiches.
A peptide of 35 amino acids in length that is at least 80% identical to FDASISQVNEKINQSLAFIRKSDELLHNVNAGKST (SEQ ID NO:2), wherein the peptide comprises a stabilized alpha-helix with non-natural amino acids comprising a hydrocarbon staple between relative positions:
- (1) i and i+3, (2) i′ and i′+4, (3) i″ and i″+7, or (4) i′ and i′+4 and i″ and i″+7 of SEQ ID NO:2, and wherein the peptide binds recombinant RSV 5-helix bundle protein.
A peptide comprising an amino acid sequence that is at least 80% identical to FDASISQVNEKINQSLAFIRKSDELLHNVNAGKST (SEQ ID NO:2), wherein either one or both of the amino acids at positions 21 and 31 of SEQ ID NO:
- 2 is unaltered, the peptide comprises a stabilized alpha-helix with non-natural amino acids comprising a hydrocarbon staple between relative positions:
- (1) i and i+3, (2) i′ and i′+4, (3) i″ and i″+7, or (4) i′ and i′+4 and i″ and i″+7 of SEQ ID NO:2, and the peptide binds recombinant RSV 5-helix bundle protein.
Dependencies are inferred from the claim text.