Small-Molecule Inhibition of Viral Fusion Glycoproteins

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. Expected final online publication date for the Annual Review of Virology, Volume 8 is September 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Membrane attachment and fusion of HIV-1, influenza A, and SARS-CoV-2: resolving the mechanisms with biophysical methods

“…The fundamental studies on viral replication including some of the literature which are reviewed in this article have been instrumental in such development. Considerable efforts are being made to design drug molecules which can neutralize the virions (Taylor et al 2021 ; Brown et al 2007 ) or target the membrane attachment and fusion of the virions (De Clercqa and Li 2016 ; Tang et al 2020 ; Bai et al 2021 ; Liu and Yang 2021 ).…”

“…The corresponding findings have contributed to the understanding of their structural and functional correlation which is central to the design of antivirals. Small molecules, peptides, and even monoclonal antibodies targeting the RBD, FP or interfering with the RBD–receptor complexation and pre-hairpin to hairpin transition have been successfully applied as antiviral drugs (De Clercq and Li 2016 ; O’Hanlon and Shaw 2019 ; Kozal et al 2020 ; Liu and Yang 2021 ; Taylor et al 2021 ).…”

“…Because of the surface representation and availability, the S protein is a major viral protein that interacts with cell surface receptors and its different epitopes are targets of antibodies produced by the human immune system. Hence, the S protein has been a prominent target for the development of antiviral drugs (Huang et al 2020 ; Liu and Yang 2021 ). Also, it is a prime antigen for designing vaccine candidates (Kyriakidis et al 2021 ).…”

Designed Ankyrin Repeat Proteins: A New Class of Viral Entry Inhibitors

“…An appealing approach is to target proteins that are involved in the fusion process, including the viral fusion proteins themselves. To date, fusion inhibitors include small molecules, peptides, nanobodies and monoclonal antibodies [ 47 , 106 , 107 , 108 , 109 ]. The modular architecture of DARPins offers new possibilities of design and opens an area of antiviral research that will certainly prove fruitful in the future.…”

Stabilisation of Viral Membrane Fusion Proteins in Prefusion Conformation by Structure-Based Design for Structure Determination and Vaccine Development

“…There is an ever-growing list of small molecule inhibitors being discovered and developed against various different viral fusion proteins. Their individual interference mechanisms in the fusion process have been covered by a recent comprehensive review [113]. Therefore, only components specifically stabilising the pre-fusion conformation of a small set of example proteins will be addressed.…”