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.
Highlights
Viral glycoproteins (GPs) mediate the initial attachment of the virion to the host cell through interaction with cell surface molecules and catalyze the membrane fusion event that allows the viral genome to be delivered to the interior of the host cell
The initial attachment step leads to endocytosis of the virion via clathrin-dependent [3, 4] or caveolin-dependent mechanisms [5,6,7], and the acidic pH of the endosomal compartment serves as the trigger for changes in the conformation of the viral fusion protein
The structural mechanism leading to membrane fusion catalyzed by class I fusion proteins includes several key steps, including (a) separation of the N-terminal head domains that make the initial contact with the receptor [24]; (b) extension of the fusion peptide (FP) toward the target membrane to form an extended intermediate [25, 26]; and (c) folding back of the C-terminal heptad repeat sequence 2 (HR2) domain against heptad repeat sequence 1 (HR1), a zipping up that brings the GP transmembrane domain (TMD) and FP together in a trimeric hairpin or, in some cases, the formation of a postfusion structure with three inner helices and three extended outer peptides
Summary
Viral glycoproteins (GPs) mediate the initial attachment of the virion to the host cell through interaction with cell surface molecules and catalyze the membrane fusion event that allows the viral genome to be delivered to the interior of the host cell. Low pH alone can trigger the structural changes necessary for membrane fusion in vitro, whereas during infection the endosomal acidification enables interaction with an intracellular entry receptor that is required for fusion and endosomal escape One such example is Lassa virus, which undergoes a pH-dependent receptor switch from the primary attachment receptor, the alpha subunit of dystroglycan, to its intracellular receptor, lysosomal-associated membrane protein 1 [10, 11]. Potential target sites for small molecules that could block fusogenic activity are generally not obvious even in highresolution structures of viral fusion proteins Despite this fundamental challenge, there are increasing examples of small molecules that exert antiviral activity by binding to a viral fusion protein and inhibiting the structural changes that are coupled to membrane fusion during viral entry. A HIV-1 entry by fusion at cell plasma membrane b Influenza virus entry by endocytosis and fusion in endosome
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