Cyclic peptide inhibitors of HIV-1 integrase derived from the LEDGF/p75 protein

被引：49

作者：

Hayouka, Zvi ^{[1
]}

Hurevich, Mattan ^{[1
]}

Levin, Aviad ^{[2
]}

Benyamini, Hadar ^{[1
]}

Iosub, Anat ^{[1
]}

Maes, Michal ^{[1
]}

Shalev, Deborah E. ^{[3
]}

Loyter, Abraham ^{[2
]}

Gilon, Chaim ^{[1
]}

Friedler, Assaf ^{[1
]}

机构：

[1] Hebrew Univ Jerusalem, Inst Chem, IL-91904 Jerusalem, Israel

[2] Hebrew Univ Jerusalem, Dept Biol Chem, IL-91904 Jerusalem, Israel

[3] Hebrew Univ Jerusalem, Wolfson Ctr Appl Struct Biol, IL-91904 Jerusalem, Israel

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2010年 / 18卷 / 23期

基金：

欧洲研究理事会; 以色列科学基金会;

关键词：

Cyclic peptides; Protein-protein interactions; Protein mimetics; NMR; HIV-1; Intergase inhibitors; RESOLVED FLUORESCENCE ANISOTROPY; DNA STRAND TRANSFER; BACKBONE CYCLIZATION; N-METHYLATION; BIOLOGICAL-ACTIVITY; TERMINAL DOMAINS; VIRUS PRODUCTION; NUCLEAR IMPORT; SUBSTANCE-P; BINDING;

D O I：

10.1016/j.bmc.2010.09.046

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：8388 / 8395

页数：8

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