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

  1. Author:
    Smith,Steven
    Zhao,Xue Zhi
    Passos, Dario Oliveira
    Pye, Valerie E.
    Cherepanov, Peter
    Lyumkis, Dmitry
    Burke,Terrence
    Hughes,Stephen

  2. Author Address

    NCI, HIV Dynam & Replicat Program, Ctr Canc Res, Frederick, MD 21702 USA.NCI, Chem Biol Lab, Ctr Canc Res, Frederick, MD 21702 USA.Salk Inst Biol Studies, Lab Genet, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA.Francis Crick Inst, Chromatin Struct & Mobile DNA Lab, London NW1 1AT, England.Imperial Coll London, Dept Infect Dis, St Marys Hosp, London W2 1PG, England.Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA.
    1. Year: 2021
    2. Date: Jun 11
  2. Journal: ACS Infectious Diseases
  3. AMER CHEMICAL SOC,
    1. 7
    2. 6
    3. Pages: 1469-1482
  5. Type of Article: Article
  6. ISSN: 2373-8227
  1. Abstract:

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

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External Sources

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  2. DOI: 10.1021/acsinfecdis.0c00819
  3. PMID: 33686850
  4. View record in Web of Science®
  5. WOS: 000662225900014

Library Notes

  1. Fiscal Year: FY2020-2021
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