Short‐peptide fusion inhibitors with high potency against wild‐type and enfuvirtide‐resistant HIV‐1
| العنوان: | Short‐peptide fusion inhibitors with high potency against wild‐type and enfuvirtide‐resistant HIV‐1 |
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| المؤلفون: | Yuxian He, Meng Zhang, Huihui Chong, Zonglin Qiu, Sheng Cui, Sandro Waltersperger, Xue Yao, Jianping Sun, Shan-Lu Liu, Meitian Wang |
| المصدر: | The FASEB Journal. 27:1203-1213 |
| بيانات النشر: | Wiley, 2012. |
| سنة النشر: | 2012 |
| مصطلحات موضوعية: | Enfuvirtide, HIV Infections, Peptide, Gp41, Biochemistry, Protein Structure, Secondary, Cell Line, Protein structure, HIV Fusion Inhibitors, Viral entry, Drug Resistance, Viral, Genetics, medicine, Humans, Molecular Biology, chemistry.chemical_classification, Cell fusion, Chemistry, HIV Envelope Protein gp41, Peptide Fragments, Protein Structure, Tertiary, N-terminus, Heptad repeat, HIV-1, Peptides, Oligopeptides, Biotechnology, medicine.drug |
| الوصف: | 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. |
| تدمد: | 1530-6860 0892-6638 |
| DOI: | 10.1096/fj.12-222547 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7001cac2807e6cff543ff9c54df56677 https://doi.org/10.1096/fj.12-222547 |
| Rights: | CLOSED |
| رقم الانضمام: | edsair.doi.dedup.....7001cac2807e6cff543ff9c54df56677 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15306860 08926638 |
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| DOI: | 10.1096/fj.12-222547 |