The N-Terminal T鈥揟 Motif of a Third-Generation HIV-1 Fusion Inhibitor Is Not Required for Binding Affinity and Antiviral Activity

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• 作者：Huihui Chong ; Zonglin Qiu ; Yang Su ; Yuxian He
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：August 27, 2015
• 年：2015
• 卷：58
• 期：16
• 页码：6378-6388
• 全文大小：652K
• ISSN：1520-4804

文摘

The highlighted next-generation HIV-1 fusion inhibitor peptide 1 is capped by two threonines. Here, we generated peptide 2 by deleting the T鈥揟 motif and compared their structural and antiviral properties. Significantly, two peptides showed similar helical and oligomeric states in solution, comparable binding affinities to the target, and no significant difference to inhibit HIV-1 fusion and infection. Also, the T鈥揟 motif was not associated with peptide 1 resistant mutations and its deletion did not affect peptide 1 against enfuvirtide-resistant HIV-1 mutants. The redundancy of the T鈥揟 motif was further verified by the model peptide C34 and short peptide inhibitors that mainly target the gp41 pocket, suggesting that the N-terminal T鈥揟 motif of peptide 1 could be removed or modified toward the development of new anti-HIV-1 drugs. Consistently, our data have verified that the M鈥揟 hook structure rather than the T鈥揟 motif is an efficient strategy for short peptide fusion inhibitors.