Effects of Single α-to-β Residue Replacements on Recognition of an Extended Segment in a Viral Fusion Protein
- 26 July 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in ACS Infectious Diseases
- Vol. 6 (8), 2017-2022
- https://doi.org/10.1021/acsinfecdis.0c00385
Abstract
Partial replacement of alpha-amino acid residues with beta-amino acid residues has been established as a strategy for preserving target-engagement by helix-forming polypeptides while altering other properties. The impact of beta-residue incorporation within polypeptides that adopt less regular conformations, however, has received less attention. The C-terminal heptad repeat (HRC) domains of fusion glycoproteins from pathogenic paramyxoviruses contain a segment that must adopt an extended conformation in order to coassemble with the N-terminal heptad repeat (HRN) domain in the postfusion state and drive a merger of the viral envelope with a target cell membrane. Here, we examine the impact of single alpha-to-beta substitutions within this extended N-terminal segment of an engineered HRC peptide designated VIQKI. Stabilities of hexameric coassemblies formed with the native human parainfluenza virus 3 (HPIV3) HRN have been evaluated, the structures of five coassemblies have been determined, and antiviral efficacies have been measured. Many sites within the extended segment show functional tolerance of alpha-to-beta substitution. These results offer a basis for future development of paramyxovirus infection inhibitors with novel biological activity profiles, possibly including resistance to proteolysis.Other Versions
Funding Information
- National Institute of Allergy and Infectious Diseases (R01AI114736, R01AI121349)
- National Institute of General Medical Sciences (F32GM122263)
This publication has 41 references indexed in Scilit:
- Therapeutic peptides: Historical perspectives, current development trends, and future directionsBioorganic & Medicinal Chemistry, 2018
- The state-of-play and future of antibody therapeuticsAdvanced Drug Delivery Reviews, 2017
- The Current State of Peptide Drug Discovery: Back to the Future?Journal of Medicinal Chemistry, 2017
- Selective and Potent Proteomimetic Inhibitors of Intracellular Protein–Protein InteractionsAngewandte Chemie-International Edition, 2015
- Peptide therapeutics: current status and future directionsDrug Discovery Today, 2015
- Inhibition of α-helix-mediated protein–protein interactions using designed moleculesNature Chemistry, 2013
- Contemporary strategies for the stabilization of peptides in the α-helical conformationCurrent Opinion in Chemical Biology, 2008
- Foldamers as versatile frameworks for the design and evolution of functionNature Chemical Biology, 2007
- Evaluation of Biologically Relevant Short α-Helices Stabilized by a Main-Chain Hydrogen-Bond SurrogateJournal of the American Chemical Society, 2006
- An Unnatural Amino Acid that Induces β-Sheet Folding and Interaction in PeptidesJournal of the American Chemical Society, 2002