HIV-1 Integrase Inhibitors with Modifications That Affect Their Potencies against Drug Resistant Integrase Mutants

• DOI: 10.1021/acsinfecdis.0c00819
• Publication Date: 2021-03-09T12:39:47Z
• Authors: Steven J. Smith; Xue Zhi Zhao; Dario Oliveira Pa...; Valerie E. Pye; Peter Cherepanov; Dmitry Lyumkis; Terrence R. Burke; Stephen H. Hughes
• Keywords: Integrase inhibitor; Affect

Integrase strand transfer inhibitors (INSTIs) block the integration step of retroviral lifecycle and are first-line drugs used for treatment HIV-1/AIDS. INSTIs have a polycyclic core with heteroatom triads, chelate metal ions at active site, halobenzyl group that interacts viral DNA attached to by flexible linker. The most broadly effective inhibit both wild-type (WT) integrase (IN) variety well-known mutants. However, because there mutations reduce potency all available INSTIs, new better compounds needed. Models based on recent structures HIV-1 red-capped mangabey SIV INs suggest modifications in INSTI could enhance interactions 3'-terminal adenosine DNA, which improve performance against resistant We designed tested series having their naphthyridine scaffold. One retained good an expanded panel IN mutants we tested. Our results possibility designing combine best features existing compounds, provide additional efficacy known