Issue 3, 2012

De novo design of small molecule inhibitors targeting the LEDGF/p75-HIVintegrase interaction

Abstract

The integration of the viral DNA into the host genome is one of the essential steps in the HIV replication cycle. This multistep process mediated by the viral enzyme integrase (IN) allows identification and development of inhibitors targeting different integrase activities. Lens epithelium-derived growth factor (LEDGF/p75) has recently been identified as a crucial cellular co-factor of integration that acts by tethering IN to the cellular chromatin. Small molecules inhibiting the LEDGF/p75-IN interaction may become new and highly active antiretroviral therapeutic agents. In this paper we report the rational design, synthesis and evaluation of inhibitors that target the LEDGF/p75 protein and compete with IN binding. These molecules are designed to mimic the integrase alpha-3 helix, which interacts with LEDGF/p75, using pharmacophore guided scaffold replacement. The inhibitor 3-(1H-indol-3-ylthio)-N-(2-isopropoxy-6-methoxypyridin-3-yl)benzamide (CAB1) and its derivatives (CAB2–13) inhibit the LEDGF/p75-IN proteinprotein interaction with moderate potency. These CAB inhibitors are the first reported example of small molecules targeting the LEDGF/p75 partner of the proteinprotein interaction, in contrast to the previously reported compounds which target the integrase partner.

Graphical abstract: De novo design of small molecule inhibitors targeting the LEDGF/p75-HIV integrase interaction

Supplementary files

Article information

Article type
Paper
Submitted
11 avg 2011
Accepted
18 okt 2011
First published
02 dec 2011

RSC Adv., 2012,2, 974-984

De novo design of small molecule inhibitors targeting the LEDGF/p75-HIV integrase interaction

C. Cavalluzzo, A. Voet, F. Christ, B. K. Singh, A. Sharma, Z. Debyser, M. D. Maeyer and E. V. D. Eycken, RSC Adv., 2012, 2, 974 DOI: 10.1039/C1RA00582K

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