The N-Terminal T-T Motif of a Third-Generation HIV-1 Fusion Inhibitor Is Not Required for Binding Affinity and Antiviral Activity.
The N-Terminal T-T Motif of a Third-Generation HIV-1 Fusion Inhibitor Is Not Required for Binding Affinity and Antiviral Activity.
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DOI：
10.1021/acs.jmedchem.5b00109
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发表时间：
2015-08
影响因子：
7.3
通讯作者：
Hui-hui Chong;Zonglin Qiu;Yang Su;Yuxian He
中科院分区：
文献类型：
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作者：
Hui-hui Chong;Zonglin Qiu;Yang Su;Yuxian He
突出显示的下一代HIV-1融合抑制剂肽1由两个苏氨酸封端。在这里，我们通过删除T-T基序产生肽2，并比较它们的结构和抗病毒性质。值得注意的是，两种肽在溶液中显示出相似的螺旋和寡聚体状态，与靶标的结合亲和力相当，并且在抑制HIV-1融合和感染方面没有显著差异。此外，T-T基序与肽1耐药突变无关，其缺失不影响肽1抗恩夫韦肽耐药HIV-1突变体。模型肽C34和主要靶向gp 41口袋的短肽抑制剂进一步验证了T-T基序的冗余性，表明肽1的N端T-T基序可以被去除或修饰，以开发新的抗HIV-1药物。因此，我们的数据证实了M-T钩结构而不是T-T基序是短肽融合抑制剂的有效策略。
The highlighted next-generation HIV-1 fusion inhibitor peptide 1 is capped by two threonines. Here, we generated peptide 2 by deleting the T-T 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-T 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-T 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-T 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-T hook structure rather than the T-T motif is an efficient strategy for short peptide fusion inhibitors.