Fusion Peptides: The Claws of the Viral Fusion Glycoproteins

Abstract Enveloped viruses, comprising highly relevant human pathogens such as human immunodeficiency (HIV), influenza (IFV) or Ebola (EBOV) viruses, have evolved a common ‘membrane fusion’ strategy to gain access to the biosynthetic resources of their host cells. The viral fusion peptides (VFPs) constitute conserved hydrophobic domains that are required for the virus–cell fusion process mediated by the viral membrane glycoproteins. A generally accepted model postulates that VFPs can exist in three states: (1) stably folded within the native glycoprotein ectodomain, (2) inserted into the membrane of the target cell, and (3) coassembled with transmembrane domains (TMDs) into membrane integral complexes. Upon fusion activation, sequential access to states (2) and (3) would enable the glycoprotein ectodomain for docking and dragging of the target cell membrane and thus promote merger. Our current understanding of the structure and function of the VFPs has potential implications for clinical intervention. Key Concepts For replication, viruses must enter into living cells and access their synthetic machinery. Enveloped viruses fuse their membrane with that of the host cell during the entry process. Envelope glycoproteins identify the host cell and induce virus–cell membrane fusion. Envelope glycoproteins access at least 3 different states: (1) pre‐fusion, in the native virion; (2) activated, when inserted both in the viral and target cell membranes; and (3) post‐fusion, the conformation adopted in the final fused membranes. Envelope glycoproteins utilise two tools to perform their function: viral fusion peptides (VFPs) that insert into the target cell membrane, and helical hairpins that bring viral and cell membranes close together. The sequences of the VFPs are overall hydrophobic, a feature conferring the capacity of inserting into membranes, and enriched in conserved Ala/Gly residues, which provides the required flexibility for function. In the pre‐fusion state of envelope glycoproteins, VFPs have been observed exposed to solvent or occluded within the trimeric complex. Synthetic VFPs are conformationally diverse in the membrane milieu. Insertion of VFPs into membranes can help fusion to evolve by restructuring the bilayer architecture locally during the process. Conserved and functional VFPs may exist in a native state accessible to drugs and biologics.