The utilization of bioactive peptides in the development of highly selective and potent pharmacologic agents for the disruption of protein-protein interactions has become more appealing for drug discovery. However, this strategy is limited by loss of bioactivity and instability to proteases.<br/>HIV-1 entry into host cell is through a fusion process that is mediated by the trimeric viral glycoprotein gp120/41 which are obtained from gp160 through proteolytic processing. Linear peptides derived from the HIV gp41 C-terminus have proven potent in inhibiting the fusion process. These peptides have shown good interaction and significant binding to the hydrophobic pocket on gp-41 N-terminus which was previously identified as a potential inhibitor site.<br/>In this study, we introduce a 23-residue C-peptide, OB-XEK22 that was optimized for HIV-1 gp-41 N-terminus binding and proteolytic stability through sulfono-γ-AApeptide substitution and all-hydrocarbon stapling. OB-XEK22 inhibited envelope-mediated membrane fusion in cell-cell fusion assays at nanomolar potency and showed improved protease resistance.

Constrained peptides that inhibit HIV-1 fusion

253rd National Meeting (2017)

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