Abstract
Fusion of lipid-enveloped viruses with the cellular plasma membrane or the endosome membrane is mediated by viral envelope proteins that undergo large conformational changes following binding to receptors. The HIV-1 fusion protein gp41 undergoes a transition into a “six-helix bundle” after binding of the surface protein gp120 to the CD4 receptor and a co-receptor. Synthetic peptides that mimic part of this structure interfere with the formation of the helix structure and inhibit membrane fusion. This approach also works with the S spike protein of SARS-CoV-2. Here we review the peptide inhibitors of membrane fusion involved in infection by influenza virus, HIV-1, MERS and SARS coronaviruses, hepatitis viruses, paramyxoviruses, flaviviruses, herpesviruses and filoviruses. We also describe recent computational methods used for the identification of peptide sequences that can interact strongly with protein interfaces, with special emphasis on SARS-CoV-2, using the PePI-Covid19 database.
Highlights
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Following receptor binding, enveloped viruses may fuse directly with the plasma membrane if their fusion machinery is active at neutral pH (e.g., human immunodeficiency virus type 1 (HIV-1), measles virus), or they may be endocytosed and fuse with the membrane of the endocytotic vesicle, if their fusion machinery requires the mild acidification of the endosome lumen facilitated by the cellular proton pump
The hemagglutinin, HA, of influenza virus, and the envelope protein of HIV-1 are Class I proteins. They are synthesized as precursor proteins that are cleaved by cellular proteases, including the transmembrane protease serine S1 member 2 (TMPRSS2) [6], forming active trimers
Summary
Virus replication can be generally divided into the early phase, which comprises attachment to the host cell, penetration and uncoating, and the late phase, which includes macromolecular synthesis, assembly and release [1,2]. The trimers are incorporated into the budding viral membrane After interacting with their receptor, and in some cases after acidification of the local environment, these proteins fold into hairpin-like structures where two alpha-helices from each monomer interact with the two-alpha helices from the other two monomers, forming the hairpin conformation. Following the interaction of gp120 with the primary cellular receptor, CD4, Env undergoes conformational changes that enable the gp120 to bind to the co-receptor (CCR5 or CXCR4, depending on the tropism of the virus) and the insertion of the fusion peptide of gp to insert its fusion peptide into the host cell membrane, initiating the fusion reaction [14,15]. The trimer undergoes further transformation when the remaining gp120 molecules bind CD4 and the co-receptor [15,16]
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