Modified human immunodeficiency virus anti-fusogenic GP41 peptides comprising a maleimide-containing group
View Patent ↗Peptides exhibiting anti-viral and anti-fusogenic activity are modified to provide greater stability and improved half-life in vivo. The selected peptides include fusion inhibitors DP178 and DP107 and related peptides and analogs thereof. The modified peptides are capable of forming covalent bonds with one or more blood components, preferably a mobile blood component.
1. A modified anti-fusogenic peptide comprising a peptide that has been modified to have a maleimide containing group coupled thereto which is reactive with a thiol group at cysteine 34 of albumin, said peptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1. SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 117, SEQ ID NO: 118, SEQ ID NO: 119, SEQ ID NO: 534, SEQ ID NO: 535, SEQ ID NO: 536, SEQ ID NO: 537, SEQ ID NO: 538, SEQ ID NO: 539, SEQ ID NO: 540, and SEQ ID NO: 541, wherein said maleimide containing group is attached to said peptide without a linker or via a (2-amino)ethoxy acetic acid (AEA) or a [2-(2-amino) ethoxy] acetic acid (AEEA) linker and said modified anti-fusogenic peptide exhibits an anti-viral and anti-fusogenic activity against human immunodeficiency virus (HIV).
2. The modified anti-fusogenic peptide of claim 1 , wherein cm said peptide is DP 178, the amino acid sequence of which is SEQ ID NO:1.
3. The modified anti-fusogenic peptide of claim 1 , wherein said peptide has an amino acid sequence selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 117, SEQ ID NO: 118, SEQ ID NO: 119, SEQ ID NO: 534, SEQ ID NO: 535, SEQ ID NO: 536, SEQ ID NO: 537, SEQ ID NO: 538, SEQ ID NO: 539, SEQ ID NO: 540, and SEQ ID NO: 541.
4. The modified anti-fusogenic peptide of claim 1 , having the formula
5. The modified anti-fusogenic peptide of claim 1 , wherein the maleimide containing group is maleimidopropionic acid (MPA) or gamma-maleimide-butyralamide (GMBA).
6. The modified anti-fusogenic peptide of claim 1 , wherein the peptide exhibits anti-viral and anti-fusogenic activity by modulation of a viral-cellular fusion process involving a coiled-coil peptide structure.
7. The modified anti-fusogenic peptide of claim 5 , wherein the peptide exhibits anti-viral and anti-fusogenic activity by modulation of a viral-cellular fusion process involving a coiled-coil peptide structure.
8. The modified anti-fusogenic peptide of claim 1 , wherein said maleimide containing group is attached to said peptide without a linker.
9. The modified anti-fusogenic peptide of claim 1 , wherein said maleimide containing group is attached to said peptide via a (2-amino)ethoxy acetic acid (AEA) or a [2-(2-amino) ethoxy] acetic acid (AEEA) linker.
10. The modified anti-fusogenic peptide of claim 1 , wherein the maleimido-containing group is coupled to the thiol group at cysteine 34 of albumin and the conjugate formed has a 1:1 molar ratio of the modified peptide to albumin.