Title: De novo design of small molecule inhibitors targeting the LEDGF/p75-HIV integrase interaction
Authors: Cavalluzzo, Claudia
Voet, Arnout
Christ, Frauke
Singh, Brajendra Kumar
Sharma, Ajendra
Debyser, Zeger
De Maeyer, Marc
Van der Eycken, Erik # ×
Issue Date: 2012
Publisher: RSC Publishing
Series Title: RSC Advances vol:2 issue:3 pages:974-984
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 protein-protein interaction with moderate potency. These CAB inhibitors are the first reported example of small molecules targeting the LEDGF/p75 partner of the protein-protein interaction, in contrast to the previously reported compounds which target the integrase partner.
ISSN: 2046-2069
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular Virology and Gene Therapy
Molecular Design and Synthesis
Biochemistry, Molecular and Structural Biology Section
× corresponding author
# (joint) last author

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