Cyclic peptide inhibitors of HIV-1 integrase derived from the LEDGF/p75 protein
Cyclic peptide inhibitors of HIV-1 integrase derived from the LEDGF/p75 protein
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DOI：
10.1016/j.bmc.2010.09.046
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发表时间：
2010-12-01
影响因子：
3.5
通讯作者：
Friedler, Assaf
中科院分区：
文献类型：
--
作者：
Hayouka, Zvi;Hurevich, Mattan;Friedler, Assaf
将线性肽限制于其生物活性构象是提高其稳定性和活性的有吸引力的方法。我们使用具有构象多样性的环状肽文库来选择活性和稳定的肽，其模拟来自其细胞辅因子LEDGF/p75（残基361-370）的HIV-1整合酶（IN）结合环的结构和活性。文库中的所有肽具有相同的一级序列，仅构象不同。文库筛选显示，环的大小和接头结构对肽的构象、结合和活性有巨大影响。其中一种环肽c（MZ 4-1）在体外和细胞中即使在8天后也是一种有效且稳定的IN活性抑制剂。c（MZ 4-1）的NMR结构表明，它获得了与LEDGF/p75中的母体位点相似的生物活性构象。(C)2010爱思唯尔有限公司版权所有。
Restricting linear peptides to their bioactive conformation is an attractive way of improving their stability and activity. We used a cyclic peptide library with conformational diversity for selecting an active and stable peptide that mimics the structure and activity of the HIV-1 integrase (IN) binding loop from its cellular cofactor LEDGF/p75 (residues 361-370). All peptides in the library had the same primary sequence, and differed only in their conformation. Library screening revealed that the ring size and linker structure had a huge effect on the conformation, binding and activity of the peptides. One of the cyclic peptides, c(MZ 4-1), was a potent and stable inhibitor of IN activity in vitro and in cells even after 8 days. The NMR structure of c(MZ 4-1) showed that it obtains a bioactive conformation that is similar to the parent site in LEDGF/p75. (C) 2010 Elsevier Ltd. All rights reserved.