Back to results
US 12,753,208 B2Granted
Antiviral structurally-stabilized Ebolavirus peptides and uses thereof
AssigneesDana-Farber Cancer Institute, Inc., The United States of America, as represented by the Secretary, Department of Health and Human Services
InventorsFederico Bernal, Amanda L. Whiting, Loren D. Walensky, Gregory H. Bird
Life of this patent
Estimating the term…
Abstract
This disclosure features structurally-stabilized Ebola virus antiviral peptides. Also disclosed are methods of using such structurally-stabilized peptides in the treatment or prevention of an Ebola virus infection or Ebola virus disease.
Claims20
A structurally stabilized peptide comprising the amino acid sequence:
- (a) HNWTKX1ITNX2INQIIHDFVNK, wherein each of X1 and X2 is independently a stapling amino acid (SEQ ID NO:15), and wherein the sidechains of X1 and X2 are cross-linked to each other;
- (b) HDWTKX1ITDX2INQIIHDFVNK, wherein each of X1 and X2 is independently a stapling amino acid (SEQ ID NO:14), and wherein the sidechains of X1 and X2 are cross-linked to each other;
- (c) X1DWTX2NITDKINQIIHDFVNK, wherein each of X1 and X2 is independently a stapling amino acid (SEQ ID NO:8), and wherein the sidechains of X1 and X2 are cross-linked to each other;
- (d) X1NWTX2NITDKINQIIHDFVNK, wherein each of X1 and X2 is independently a stapling amino acid (SEQ ID NO:9), and wherein the sidechains of X1 and X2 are cross-linked to each other;
- (e) HX1WTKX2ITDKINQIIHDFVNK, wherein each of X1 and X2 is independently a stapling amino acid (SEQ ID NO:11), and wherein the sidechains of X1 and X2 are cross-linked to each other;
- (f) HNWTX1NITX2KINQIIHDFVNK, wherein each of X1 and X2 is independently a stapling amino acid (SEQ ID NO:12), and wherein the sidechains of X1 and X2 are cross-linked to each other;
- (g) HDWTX1NITX2KINQIIHDFVNK, wherein each of X1 and X2 is independently a stapling amino acid (SEQ ID NO:13), and wherein the sidechains of X1 and X2 are cross-linked to each other;
- (h) HX1WTKNITX2KIDQIIHDFVNK, wherein each of X1 and X2 is independently a stapling amino acid (SEQ ID NO:20), and wherein the sidechains of X1 and X2 are cross-linked to each other;
- or
- (i) HX1WTKNITX2KINQIIHDFVNK, wherein each of X1 and X2 is independently a stapling amino acid (SEQ ID NO:21), and wherein the sidechains of X1 and X2 are cross-linked to each other;
- or a pharmaceutically acceptable salt thereof;
- and wherein the structurally stabilized peptide is 21-50 amino acids in length.
9 more elements
A structurally stabilized peptide comprising:
- (a) an amino acid sequence set forth in SEQ ID NO:2 except with 3 to 12 amino acid substitutions and 0 to 5 deletions from the N-terminus, the C-terminus, or a combination thereof, of the amino acid sequence set forth in SEQ ID NO:2, or a pharmaceutically acceptable salt thereof;
- wherein the structurally stabilized peptide comprises amino acid substitutions at the following positions (relative to SEQ ID NO:2) with non-natural amino acids with olefinic side chains:
- (i) 2 and 6;
- (ii) 2 and 9;
- (iii) 6 and 10;
- (iv) 1 and 8;
- or
- (v) 12 and 16;
- wherein one or more aspartic acid at positions 2, 9, 12, 17 and 20 in SEQ ID NO:
- 2 is substituted by asparagine, wherein the structurally stabilized peptide binds to a 5 helix bundle or fusion bundle intermediate of EBOV GP2, wherein the structural stabilization comprises a hydrocarbon staple or stitch, and wherein the structurally stabilized is 16-50 amino acids in length;
- or
- (b) an amino acid sequence set forth in any one of SEQ ID NOs:
- 2-6 except with 2 to 13 amino acid substitutions and 0 to 5 deletions from the N-terminus, the C-terminus, or a combination thereof, of the amino acid sequence set forth in any one of SEQ ID NOs:
- 2-6, or a pharmaceutically acceptable salt thereof;
- wherein the structurally stabilized peptide comprises amino acid substitutions at the following positions (relative to SEQ ID NO:2) with non-natural amino acids with olefinic side chains cross-linked to each other:
- (i) 2 and 6;
- (ii) 2 and 9;
- (iii) 6 and 10;
- (iv) 1 and 8;
- or
- (vi) 12 and 16;
- wherein the structurally stabilized peptide does not comprise the amino acids corresponding to positions 610-612 of SEQ ID NO:
- 1, wherein at least one of the amino acids at positions 2, 9, 12, 17 and 20 (numbering with respect to SEQ ID NO:2) is asparagine, wherein the structurally stabilized peptide binds to a 5 helix bundle or fusion bundle intermediate of EBOV GP2;
- and wherein the structurally stabilized is 16-50 amino acids in length.
21 more elements
A peptide comprising an amino acid sequence:
- (a) HNWTKX1ITNX2INQIIHDFVNK, wherein each of X1 and X2 is independently a stapling amino acid (SEQ ID NO:15);
- (b) HDWTKX1ITDX2INQIIHDFVNK, wherein each of X1 and X2 is independently a stapling amino acid (SEQ ID NO:14);
- (c) X1DWTX2NITDKINQIIHDFVNK, wherein each of X1 and X2 is independently a stapling amino acid (SEQ ID NO:8);
- (d) X1NWTX2NITDKINQIIHDFVNK, wherein each of X1 and X2 is independently a stapling amino acid (SEQ ID NO:9);
- (e) HX1WTKX2ITDKINQIIHDFVNK, wherein each of X1 and X2 is independently a stapling amino acid (SEQ ID NO:11);
- (f) HNWTX1NITX2KINQIIHDFVNK, wherein each of X1 and X2 is independently a stapling amino acid (SEQ ID NO:12);
- (g) HDWTX1NITX2KINQIIHDFVNK, wherein each of X1 and X2 is independently a stapling amino acid (SEQ ID NO:13);
- (h) HX1WTKNITX2KIDQIIHDFVNK, wherein each of X1 and X2 is independently a stapling amino acid (SEQ ID NO:20);
- or
- (i) HX1WTKNITX2KINQIIHDFVNK, wherein each of X1 and X2 is independently a stapling amino acid (SEQ ID NO:21);
- and
- wherein the peptide binds a 5 helix bundle or fusion bundle intermediate of EBOV GP2,
- wherein the peptide is 21 to 50 amino acids in length.
10 more elements
A method of making a structurally stabilized peptide, the method comprising:
- (a) providing a peptide having comprising the amino acid sequence set forth in any one of SEQ ID NOs:
- 8, 9, 11-15, 20, 21, 26, 27, 29-33, 38, and 39, and (b) cross-linking the peptide to make a structurally stabilized peptide.
Dependencies are inferred from the claim text.