Article Metrics


Online attention

HIV-1 integrase inhibitors with modifications that affect their potencies against drug resistant integrase mutants

DOI: 10.1021/acsinfecdis.0c00819 DOI Help

Authors: Steven J. Smith (National Cancer Institute) , Xue Zhi Zhao (National Cancer Institute) , Dario Oliveira Passos (he Salk Institute for Biological Studies) , Valerie E. Pye (The Francis Crick Institute (Midland Road)) , Peter Cherepanov (The Francis Crick Institute; Imperial College London) , Dmitry Lyumkis (The Salk Institute for Biological Studies; The Scripps Research Institute) , Terrence R. Burke (National Cancer Institute) , Stephen H. Hughes (National Cancer Institute)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Infectious Diseases , VOL 11

State: Published (Approved)
Published: March 2021
Diamond Proposal Number(s): 13775

Open Access Open Access

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.

Journal Keywords: integrase; strand transfer; inhibition; potency; mutant; susceptibility

Diamond Keywords: Human Immunodeficiency Virus (HIV); Viruses

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I03-Macromolecular Crystallography

Added On: 14/03/2021 22:15


Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)