HIV nucleocapsid proteins as targets for novel 1,2-benzisothiazol-3(2H)-one benzenesulfonamides: synthesis and antiretroviral activity
Roberta Loddo, Matteo Incerti, Elda Favari, Valeria Manca, Marta Cogoni, Rebecca Piras, Luca Virdis, Vanessa Palmas, Elena Tamburini, Paolo La Colla, Giuseppina Sanna
TL;DR
A new class of antiretroviral compounds was developed that targets HIV nucleocapsid proteins and shows activity against multiple HIV strains.
Contribution
The discovery of a new class of antiretroviral agents targeting HIV nucleocapsid proteins with a novel mode of action.
Findings
Compound 6 inhibits replication of HIV-1, HIV-2, and drug-resistant HIV-1 variants.
Compound 6 does not inhibit HIV-1 reverse transcriptase or integrase.
Resistance mutations to compound 6 are found in the gag region encoding nucleocapsid proteins.
Abstract
A new class of 1,2-benzisothiazol-3(2H)-one benzenesulfonamides has been synthesized. In cell-based assays, the lead compound 6 inhibits the replication of HIV-1, HIV-2, and HIV-1 variants carrying clinically relevant mutations against non-nucleoside, nucleoside, and protease inhibitors. In enzyme assays, compound 6 does not inhibit HIV-1 reverse transcriptase and integrase. Genome sequencing of HIV-1 mutants selected for resistance to compound 6 reveals no mutations in the pol or env genes. Instead, two mutations are mapped in the gag region, which encodes nucleocapsid (NC) proteins involved in early and late key processes of retrovirus replication, suggesting that NC proteins are the target of the title compounds. Compound 6 shows concentration-dependent virucidal activity against cell-free HIV-1 and HIV-2. Benzisothiazol-3(2H)-one benzenesulfonamides are a new class of antiretroviral…
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Taxonomy
TopicsHIV/AIDS drug development and treatment · Synthesis and biological activity · HIV Research and Treatment