Cell-Free HIV-1 Virucidal Action by Modified Peptide Triazole Inhibitors of Env gp120

摘要

Initial entry of human immunodeficiency virus-1 (HIV-1) into host cells remains a compelling and yet elusive target for developing agents to prevent infection. This step is mediated by a sequence of interactions of a trimeric gp120/gp41 envelope (Env) protein complex with host cells, including initial gp120 encounter with the cellular receptor CD4 and a chemokine co-receptor, usually CCR5 or CXCR4. A peptide triazole class of entry inhibitor leads has been shown to bind to gp120 with close to nanomolar affinity, to suppress protein-ligand interactions of the Env protein at both its CD4 and co-receptor binding sites, and to inhibit cell infection by a broad range of virus subtypes. These inhibitors appear to function mechanistically by entrapping gp120 in an inactivated conformation, different from either the flexible ground state of gp120 or the highly structured CD4-activated state. This entrapment effectively halts the entry process at the initial binding stages.