Sulfono-γ-AA modified peptides that inhibit HIV-1 fusion

Abstract

The utilization of bioactive peptides in the development of highly selective and potent pharmacological agents for the disruption of protein-protein interactions is appealing for drug discovery. It is known that HIV-1 entry into a host cell is through a fusion process that is mediated by the trimeric viral glycoprotein gp120/41, which is derived from gp160 through proteolytic processing. Peptides derived from the HIV gp41 C-terminus have proven to be potent in inhibiting the fusion process. These peptides bind tightly to the hydrophobic pocket on the gp-41 N-terminus, which was previously identified as a potential inhibitor binding site. In this study, we introduce modified 23-residue C-peptides, 3 and 4, bearing a sulfono-γ-AA residue substitution and hydrocarbon stapling, respectively, which were developed for HIV-1 gp-41 N-terminus binding. Intriguingly, both 3 and 4 were capable of inhibiting envelope-mediated membrane fusion in cell-cell fusion assays at nanomolar potency. Our study reveals that sulfono-γ-AA modified peptides could be used for the development of more potent anti-HIV agents.

Figure 1.

(A) Schematic illustration of the different regions of HIV-1 gp41. FP: Fusion peptide, N-HR: N Heptad Repeat, C-HR: C Heptad Repeat, MPER: Membrane Proximal Ectodomain Region, TM: Transmembrane region, CP: cytoplasmic domain and (B) C-HR derived peptides. “X” shows the position of the hydrocarbon staple; “γK” is sulfono-γAA-Lysine. Peptide 1 is MT-SC22EK and was first reported in ref.

Figure 2.

A. Schematic illustration of the helical wheel of the C-terminal Heptad repeat of gp-41. B. General structures of α-peptides, γ-AApeptides and sulfono- γ-AApeptides. C. Schematic illustration of the positioning of the hydrocarbon staple and sulfono-γAA1.

Figure 3

(A) CD spectra of peptides 1–4 (B) Change in mean residue ellipticity [θ] _222nm for peptides 1–4 as a function of temperature (5–70°C).Conditions – pH 7,25°C,Solvent – H₂0