Rational Design of Sulfonyl-γ-AApeptides as Highly Potent HIV‑1 Fusion Inhibitors with Broad-Spectrum Activity

The HIV-1 epidemic has significant social and economic
implications
for public health. Developing new antivirus drugs to eradicate drug
resistance is still urgently needed. Herein, we demonstrated that
sulfonyl-γ-AApeptides could be designed to mimic MTSC22EK, one
potent HIV fusion inhibitor derived from CHR. The best two sequences
revealed comparable activity to MTSC22EK in an authentic HIV-1 infection
assay and exhibited broad-spectrum anti-HIV-1 activity to many HIV-1
clinical isolates. Furthermore, sulfonyl-γ-AApeptides show remarkable
resistance to proteolysis and favorable permeability in PAMPA-GIT
and PAMPA-BBB assays, suggesting that both sequences could control
HIV-1 within the central nervous system and possess promising oral
bioavailability. Mechanistic investigations suggest that these sulfonyl-γ-AApeptides
function by mimicking the CHR of gp41 and tightly bind with NHR, thereby
inhibiting the formation of the 6-HB structure necessary for HIV-1
fusion. Overall, our results suggest that sulfonyl-γ-AApeptides
represent a new generation of anti-HIV-1 fusion inhibitors. Moreover,
this design strategy could be adopted to modulate many of the PPIs.