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Publication Abstract from PubMed

SC29EK is an electronically constrained alpha-helical peptide HIV-1 fusion inhibitor highly effective against both wild-type and enfuvirtide (T20)-resistant viruses. In this study, we focused on investigating the mechanism of HIV-1 resistance to SC29EK by two approaches. First, SC29EK-escaping HIV-1 variants were selected and characterized. Three mutant viruses, which possessed two (E43K/E49A) or three (Q39R/N43K/N126K, N43K/E49A/N126K) amino acid substitutions in the N- and C-terminal repeat regions of gp41 were identified as conferring high resistance to SC29EK and cross-resistance to the first-generation (T20, C34) and newly-designed (sifuvirtide, MT-SC29EK, 2P23) fusion inhibitors. The resistance mutations could reduce the binding stability of SC29EK, impair the ability of viral Env-mediated cell fusion and entry, and change the conformation of the gp41 core structure. Further, we determined the crystal structure of SC29EK in complex with a target mimic peptide, which revealed the critical intra- and inter-helical interactions underlying the mode of action of SC29EK and the genetic pathway to HIV-1 resistance. Taken together, the present data provide new insights for the structure and function of gp41 and the structure-activity relationship (SAR) of viral fusion inhibitors.IMPORTANCE T20 is the only membrane fusion inhibitor available for treatment of viral infection, but it has relatively low anti-HIV activity and genetic barrier for resistance, thus calling for new drugs blocking the viral fusion process. As an electronically constrained alpha-helical peptide, SC29EK is highly potent on both wild-type and T20-resistant HIV-1 strains. Here, we report the characterization of HIV-1 variants resistant to SC29EK and the crystal structure of SC29EK. The key mutations mediating high resistance to SC29EK and cross-resistance to the first- and new-generations of fusion inhibitors as well as the underlying mechanisms were identified. The crystal structure of SC29EK bound to a target mimic peptide further revealed its action mode and genetic pathway to inducing resistance. Hence, our data have shed new lights on the mechanisms of HIV-1 fusion and its inhibition.

Mechanism of HIV-1 Resistance to an Electronically Constrained alpha-Helical Peptide Membrane Fusion Inhibitor.,Wu X, Liu Z, Ding X, Yu D, Wei H, Qin B, Zhu Y, Chong H, Cui S, He Y J Virol. 2018 Jan 10. pii: JVI.02044-17. doi: 10.1128/JVI.02044-17. PMID:29321334^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.