Effects of Single α-to-β Residue Replacements on Recognition of an Extended Segment in a Viral Fusion Protein

Partial replacement of α-amino acid residues with β-amino acid residues has been established as a strategy for preserving target-engagement by helix-forming polypeptides while suppressing susceptibility to proteolysis. The impact of β-residue incorporation within polypeptides that adopt less regular conformations, however, has received less attention. The HRC domains of fusion glycoproteins from pathogenic paramyxoviruses contain a segment that must adopt an extended conformation in order to engage the HRN domain in the post-fusion state and drive merger of the viral envelope with a target cell membrane. Here we examine the impact of single α-to-β substi-tutions within this extended N-terminal segment of the engineered HRC peptide VIQKI. Stabilities of helix-bundles formed with a native viral HRN have been evaluated, the structures of five helix-bundles have been determined, and antiviral efficacies have been measured. Many sites within the extended segment show functional tolerance of α-to-β substitution. These results offer a basis for future develop-ment of protease-resistant inhibitors of paramyxovirus infection.