New Class of HIV-1 Integrase (IN) Inhibitors with a Dual Mode of Action

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2012 Apr 27

PMID 22535962

Citations 96

Authors

Manuel Tsiang

Gregg S Jones

Anita Niedziela-Majka

Elaine Kan

Eric B Lansdon

Wayne Huang

Magdeleine Hung

Dharmaraj Samuel

Nikolai Novikov

Yili Xu

Michael Mitchell

Hongyan Guo

Kerim Babaoglu

Xiaohong Liu

Romas Geleziunas

Roman Sakowicz

Affiliations

Soon will be listed here.

Abstract

tert-Butoxy-(4-phenyl-quinolin-3-yl)-acetic acids (tBPQA) are a new class of HIV-1 integrase (IN) inhibitors that are structurally distinct from IN strand transfer inhibitors but analogous to LEDGINs. LEDGINs are a class of potent antiviral compounds that interacts with the lens epithelium-derived growth factor (LEDGF) binding pocket on IN and were identified through competition binding against LEDGF. LEDGF tethers IN to the host chromatin and enables targeted integration of viral DNA. The prevailing understanding of the antiviral mechanism of LEDGINs is that they inhibit LEDGF binding to IN, which prevents targeted integration of HIV-1. We showed that in addition to the properties already known for LEDGINs, the binding of tBPQAs to the IN dimer interface inhibits IN enzymatic activity in a LEDGF-independent manner. Using the analysis of two long terminal repeat junctions in HIV-infected cells, we showed that the inhibition by tBPQAs occurs at or prior to the viral DNA 3'-processing step. Biochemical studies revealed that this inhibition operates by compound-induced conformational changes in the IN dimer that prevent proper assembly of IN onto viral DNA. For the first time, tBPQAs were demonstrated to be allosteric inhibitors of HIV-1 IN displaying a dual mode of action: inhibition of IN-viral DNA assembly and inhibition of IN-LEDGF interaction.

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