Discovery of arylsulfonamides as a novel class of allosteric integrase inhibitors with antiviral activity.

Bioorganic & medicinal chemistry letters 2023 Jun 01

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Lens epithelial-derived growth factor (LEDGF) increases the efficiency of proviral DNA integration into the host genome by interacting with HIV integrase (IN) and directing it to a chromatin environment that favors viral transcription. Allosteric integrase inhibitors (ALLINIs), such as known 2-(tert-butoxy)acetic acid (1), bind to the LEDGF pocket on the catalytic core domain (CCD) of IN, but exert more potent antiviral activities by inhibition of late-stage HIV-1 replication events than through disruption of proviral integration at an earlier phase. A high-throughput screen (HTS) for compounds that disrupt IN-LEDGF interaction led to the identification of a novel arylsulfonamide series, as exemplified by 2, possessing ALLINI-like properties. Further SAR studies led to more potent compound 21 and provided key chemical biology probes revealing that arylsulfonamides are a novel class of ALLINIs with a distinct binding mode than that of 2-(tert-butoxy)acetic acids. Copyright © 2023 Elsevier Ltd. All rights reserved.

Citation

Cheng Wang, Gregory C Adam, Christine Burlein, Steven Carroll, William Dankulich, Tracy Diamond, Jay Grobler, Jeffrey Heath, Adam Johnson, Daniel Klein, Daniel Krosky, Kartik Narayan, Yangsi Ou, John Sanders, Sujata Sharma, Min Xu, Antonella Converso. Discovery of arylsulfonamides as a novel class of allosteric integrase inhibitors with antiviral activity. Bioorganic & medicinal chemistry letters. 2023 Jun 01;89:129303