Helical sulfonyl-γ-AApeptides for the inhibition of HIV-1 fusion and HIF-1α signaling

Abstract

Synthetic helical peptidic foldamers show promising applications in chemical biology and biomedical sciences by mimicking protein helical segments. Sulfonyl-γ-AApeptide helices developed by our group exhibit good chemodiversity, predictable folding structures, proteolytic resistance, favorable cell permeability, and enhanced bioavailability. Herein, in this minireview, we highlight two recent examples of homogeneous left-handed sulfonyl-γ-AApeptide helices to modulate protein-protein interactions (PPIs). One is sulfonyl-γ-AApeptides as anti-HIV-1 fusion inhibitors mimicking the helical C-terminal heptad repeat (CHR), which show excellent anti-HIV-1 activities through tight binding with the N-terminal heptad repeat (NHR) and inhibiting the formation of the 6-helical bundle (HB) structure. Another example is helical sulfonyl-γ-AApeptides disrupting hypoxia-inducible factor 1α (HIF-1α) and p300 PPI, thus selectively inhibiting the relevant signaling cascade. We hope these findings could help to elucidate the principles of the structural design of sulfonyl-γ-AApeptides and inspire their future applications in PPI modulations.

Fig. 1. Comparison between the natural helical peptide and sulfonyl-γ-AApeptide.

Fig. 2. A. The chemical structure of the sulfonyl-γ-AApeptide building block. B. Crystal structure of a random l-sulfonyl-γ-AApeptide sequence. C. Top view of crystal structure B, showing four binding surfaces: a–d.

Fig. 3. A. The top view of the crystal structure of the 6-HB bundle (PDB 1AIK), CHR domain in green and NHR domain in white. B. The side view. C. Binding interactions in key residues of CHR (green) with NHR. Reproduced from ref. with permission from American Chemical Society, copyright 2023.

Fig. 4. A (1). Structure of MTSC22EK showing the crucial binding residues. (2) Structure of sulfonyl-γ-AApeptide mimetic 12 showing crucial binding residues. (3) The overlap of structure (1) and (2). (4) Binding interaction between MTSC22EK and the NHR domain. (5) Binding interaction between mimetic 12 and the NHR domain. (6) The overlap in the binding model. B. The chemical structures of a few representative sequences. The crucial binding side chains are shown in red. Peptide 1 is MTSC22EK. C. Anti-HIV-1 activities (IC₅₀) for inhibiting HIV-1 IIIB strain replication and half-maximal cytotoxicity concentration (CC₅₀) of sulfonyl-γ-AApeptides and T20 (enfuvirtide, FDA-approved HIV-1 fusion inhibitor). SI = CC₅₀/IC₅₀. Reproduced from ref. with permission from American Chemical Society, copyright 2023.

Fig. 5. A. HIF-1α/p300-mediated hypoxia-inducible signaling pathways. B Structure of the HIF-1α/p300 complex (PDB: 1L3E) and sequence of HIF-1α CTAD (776–826). Reproduced from ref. with permission from American Chemical Society, copyright 2023.

Fig. 6. A. Structure of helix C with key residues in red. B. Interaction between helix C and p300. C. Structure of sulfonyl-γ-AApeptide mimic HC11 and the overlap of HC11/helix C. D. Structure of mimic HC13 and the overlap of HC13/helix C. Reproduced from ref. with permission from American Chemical Society, copyright 2023.