title: Short-peptide fusion inhibitors with high potency against wild-type and enfuvirtide-resistant HIV-1.
abstract: Peptides derived from the C-terminal heptad repeat (C peptides) of HIV-1 gp41 are potent inhibitors against virus entry. However, development of a short C peptide possessing high anti-HIV potency is considered a daunting challenge. We recently discovered that the residues Met626 and Thr627 preceding the pocket-binding domain of the C peptide adopt a unique M-T hook structure that is crucial for the design of HIV-1 fusion inhibitors. In this study, we first presented a proof-of-concept prototype that the M-T hook residues can dramatically improve the antiviral activity and thermostability of a short C peptide. We then generated a 24-mer peptide termed MT-SC22EK by incorporating the M-T hook structure to the N terminus of the poorly active short C peptide SC22EK. Amazingly, MT-SC22EK inhibited HIV-1-mediated cell fusion and infection at a level comparable to C34, T1249, SC29EK, and sifuvirtide, and it was highly active against diverse HIV-1 subtypes and variants, including those T20 (enfuvirtide) and SC29EK-resistant viruses. The high-resolution crystal structure of MT-SC22EK reveals the N-terminal M-T hook conformation folded by incorporated Met626 and Thr627 and identifies the C-terminal boundary critical for the anti-HIV activity. Collectively, our studies provide new insights into the mechanisms of HIV-1 fusion and its inhibition.
authors.affiliation: Chinese Academy of Medical Sciences, 9 Dong Dan San Tiao, Beijing 100730, China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Chong
authors.forename: Xue
authors.initials: X
authors.lastname: Yao
authors.forename: Zonglin
authors.initials: Z
authors.lastname: Qiu
authors.forename: Jianping
authors.initials: J
authors.lastname: Sun
authors.forename: Meng
authors.initials: M
authors.lastname: Zhang
authors.forename: Sandro
authors.initials: S
authors.lastname: Waltersperger
authors.forename: Meitian
authors.initials: M
authors.lastname: Wang
authors.forename: Shan-Lu
authors.initials: SL
authors.lastname: Liu
authors.forename: Sheng
authors.initials: S
authors.lastname: Cui
authors.forename: Yuxian
authors.initials: Y
authors.lastname: He
mesh_terms: D002460:Cell Line; D024882:Drug Resistance, Viral / Q000187:drug effects*; D000077560:Enfuvirtide; D015700:HIV Envelope Protein gp41 / Q000737:chemistry* / Q000378:metabolism; D023581:HIV Fusion Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010446:Peptide Fragments; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D009842:Oligopeptides; D010446:Peptide Fragments; D010455:Peptides; C540660:SC29EK peptide; C514787:gp41 protein, Human immunodeficiency virus 1; D000077560:Enfuvirtide