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

• Published in: Molecules (Basel, Switzerland) Vol. 24; no. 20; p. 3675
• Main Authors: Aknin, Cindy, Smith, Elena A, Marchand, Christophe, Andreola, Marie-Line, Pommier, Yves, Metifiot, Mathieu
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 12.10.2019; MDPI
• Subjects: Acquired immune deficiency syndrome; AIDS; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Binding sites; Catalytic Domain - drug effects; Cations; Chemotherapy; Cross-resistance; Deoxyribonucleic acid; DNA; dna-binding inhibitor; drug discovery; Drug dosages; Drug Resistance, Viral; Enzymes; High-throughput screening; High-Throughput Screening Assays; HIV; HIV - drug effects; HIV - enzymology; HIV - pathogenicity; HIV Infections - drug therapy; HIV Infections - enzymology; HIV Infections - virology; HIV Integrase - genetics; HIV Integrase Inhibitors - chemistry; HIV Integrase Inhibitors - pharmacology; hiv-1; Human immunodeficiency virus; Humans; Inhibitors; insti resistance; Integrase; Life Sciences; Magnesium; Microbiology and Parasitology; Mutation; Stilbene; Viral infections; Virology; Virus Replication - drug effects; HIV-1; INSTI resistance; DNA-binding inhibitor; drug discovery; high-throughput screening
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules24203675

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 -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.