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Open AccessArticle

Discovery of Novel Integrase Inhibitors Acting outside the Active Site Through High-Throughput Screening

1
Laboratoire MFP, CNRS UMR5234, Université de Bordeaux, 146 rue Léo Saignat, 33076 Bordeaux CEDEX, France
2
Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, CCR, NCI, NIH, 37 Convent Drive, Bethesda, MD 20892, USA
*
Author to whom correspondence should be addressed.
Present addresses: Quality Control, Protein Sciences, A Sanofi Company, 1000 Research Parkway, Meriden, CT 06450, USA.
Present addresses: Center for Research Strategy, NCI, NIH, 31 Center Drive, Bethesda, MD 20892, USA.
Molecules 2019, 24(20), 3675; https://doi.org/10.3390/molecules24203675
Received: 20 September 2019 / Revised: 3 October 2019 / Accepted: 9 October 2019 / Published: 12 October 2019
(This article belongs to the Special Issue Trends in the Development of Enzyme Inhibitors)
Currently, an increasing number of drugs are becoming available to clinics for the treatment of HIV infection. Even if this targeted therapy is highly effective at suppressing viral replication, caregivers are facing growing therapeutic failures in patients, due to resistance with or without treatment adherence concerns. Accordingly, it is important to continue to discover small molecules that have a novel mechanism of inhibition. In this work, HIV integrase inhibitors were selected by high-throughput screening. Chemical structure comparisons enabled the identification of stilbene disulfonic acids as a potential new chemotype. Biochemical characterization of the lead compound stilbenavir (NSC34931) and a few derivatives was performed. Stilbene disulfonic acid derivatives exhibit low to sub-micromolar antiviral activity, and they inhibit integrase through DNA-binding inhibition. They probably bind to the C-terminal domain of integrase, in the cavity normally occupied by the noncleaved strand of the viral DNA substrate. Because of this original mode of action compared to active site strand transfer inhibitors, they do not exhibit cross-resistance to the three main resistance pathways to integrase inhibitors (G140S-Q148H, N155H, and Y143R). Further structure–activity optimization should enable the development of more active and less toxic derivatives with potential clinical relevance. View Full-Text
Keywords: HIV-1; INSTI resistance; DNA-binding inhibitor; high-throughput screening; drug discovery HIV-1; INSTI resistance; DNA-binding inhibitor; high-throughput screening; drug discovery
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MDPI and ACS Style

Aknin, C.; Smith, E.A.; Marchand, C.; Andreola, M.-L.; Pommier, Y.; Metifiot, M. Discovery of Novel Integrase Inhibitors Acting outside the Active Site Through High-Throughput Screening. Molecules 2019, 24, 3675.

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