Small Molecule Inhibitors of the LEDGF Site of Human Immunodeficiency Virus Integrase Identified by Fragment Screening and Structure Based Design

被引：48

作者：

Peat, Thomas S. ^{[1
]}

Rhodes, David I. ^{[2
]}

Vandegraaff, Nick ^{[2
]}

Le, Giang ^{[2
]}

Smith, Jessica A. ^{[2
]}

Clark, Lisa J. ^{[2
]}

Jones, Eric D. ^{[2
]}

Coates, Jonathan A. V. ^{[2
]}

Thienthong, Neeranat ^{[2
]}

Newman, Janet ^{[1
]}

Dolezal, Olan ^{[1
]}

Mulder, Roger ^{[3
]}

Ryan, John H. ^{[3
]}

Savage, G. Paul ^{[3
]}

Francis, Craig L. ^{[3
]}

Deadman, John J. ^{[2
]}

机构：

[1] CSIRO Mat Sci & Engn, Parkville, Vic, Australia

[2] Avexa Ltd, Melbourne, Vic, Australia

[3] CSIRO Mat Sci & Engn, Clayton, Vic, Australia

来源：

PLOS ONE | 2012年 / 7卷 / 07期

关键词：

HIV-1; INTEGRASE; CATALYTIC DOMAIN; BINDING DOMAIN; RALTEGRAVIR; MECHANISM; PROTEIN; MODEL; CORE;

D O I：

10.1371/journal.pone.0040147

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

A fragment-based screen against human immunodeficiency virus type 1 (HIV) integrase led to a number of compounds that bound to the lens epithelium derived growth factor (LEDGF) binding site of the integrase catalytic core domain. We determined the crystallographic structures of complexes of the HIV integrase catalytic core domain for 10 of these compounds and quantitated the binding by surface plasmon resonance. We demonstrate that the compounds inhibit the interaction of LEDGF with HIV integrase in a proximity AlphaScreen assay, an assay for the LEDGF enhancement of HIV integrase strand transfer and in a cell based assay. The compounds identified represent a potential framework for the development of a new series of HIV integrase inhibitors that do not bind to the catalytic site of the enzyme.

引用

页数：11

共 49 条

[1] THE CCP4 SUITE - PROGRAMS FOR PROTEIN CRYSTALLOGRAPHY [J].