Enveloped Virus Entry as a Pharmacological Target: Viral Membrane Fusion Machineries and Their Inhibitors

Enveloped virus entry into the host cell mediated by the viral fusion glycoproteins represents an earliest step in viral infection, the inhibition of which offers a number of advantages over the antivirals with other mechanisms of action. Viral glycoproteins are classified into three classes with rather different structures, but, despite that, they share some functional features, such as the separation of receptor recognition/ binding function and membrane fusion function into two different subunits or domains. All of them are transmembrane proteins anchored in the virions membrane, and possessing a hydrophobic structure (fusion peptide or fusion loop), which is inserted in target cell membrane early in fusion. Here, we describe the membrane fusion machinery of all 3 classes of viral glycoproteins and indicate their domains and structures, which can serve as the targets for entry inhibitors with different mechanisms of action. The examples of large and small molecule entry inhibitors belonging to the groups of affinity blockers, inhibitors of glycoprotein-receptor binding, fusion inhibitors, anchor inhibitors and compounds blocking the function of membrane-proximal external region (MPER) of viral glycoproteins are provided. Finally, the perspectives of developing broadly acting entry inhibitors are discussed.