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.
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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)
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Chemical References |
- HIV Envelope Protein gp41
- HIV Fusion Inhibitors
- Oligopeptides
- Peptide Fragments
- Peptides
- SC29EK peptide
- gp41 protein, Human immunodeficiency virus 1
- Enfuvirtide
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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
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