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: Huihui Chong, Xue Yao, Zonglin Qiu, Jianping Sun, Meng Zhang, Sandro Waltersperger, Meitian Wang, Shan-Lu Liu, Sheng Cui, Yuxian He
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 27 Issue 3 Pg. 1203-13 (Mar 2013) ISSN: 1530-6860 [Electronic] United States
• PMID: 23233535 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• HIV Envelope Protein gp41
• HIV Fusion Inhibitors
• Oligopeptides
• Peptide Fragments
• Peptides
• SC29EK peptide
• gp41 protein, Human immunodeficiency virus 1
• Enfuvirtide

Topics

• Cell Line
• Drug Resistance, Viral (drug effects)
• Enfuvirtide
• HIV Envelope Protein gp41 (chemistry, metabolism)
• HIV Fusion Inhibitors (chemical synthesis, chemistry, pharmacology)
• HIV Infections (drug therapy)
• HIV-1 (chemistry, metabolism)
• Humans
• Oligopeptides (chemical synthesis, chemistry, pharmacology)
• Peptide Fragments
• Peptides (chemistry, pharmacology)
• Protein Structure, Secondary
• Protein Structure, Tertiary