Small-Molecule Inhibition of Viral Fusion Glycoproteins

Annu Rev Virol. 2021 Sep 29;8(1):459-489. doi: 10.1146/annurev-virology-022221-063725. Epub 2021 Jul 1.

Abstract

Viral fusion glycoproteins catalyze membrane fusion during viral entry. Unlike most enzymes, however, they lack a conventional active site in which formation or scission of a specific covalent bond is catalyzed. Instead, they drive the membrane fusion reaction by cojoining highly regulated changes in conformation to membrane deformation. Despite the challenges in applying inhibitor design approaches to these proteins, recent advances in knowledge of the structures and mechanisms of viral fusogens have enabled the development of small-molecule inhibitors of both class I and class II viral fusion proteins. Here, we review well-validated inhibitors, including their discovery, targets, and mechanism(s) of action, while highlighting mechanistic similarities and differences. Together, these examples make a compelling case for small-molecule inhibitors as tools for probing the mechanisms of viral glycoprotein-mediated fusion and for viral glycoproteins as druggable targets.

Keywords: antiviral; fusion inhibitor; inhibitor design; small molecule; viral fusion.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Membrane Fusion
  • Viral Envelope Proteins / metabolism
  • Viral Fusion Proteins* / chemistry
  • Virus Internalization*

Substances

  • Viral Envelope Proteins
  • Viral Fusion Proteins