Download MendeleyThe structural and mechanistic bases for the viral resistance to allosteric HIV-1 integrase inhibitor pirmitegravir.
Dinh, T., Tber, Z., Rey, J.S., Mengshetti, S., Annamalai, A.S., Haney, R., Briganti, L., Amblard, F., Fuchs, J.R., Cherepanov, P., Kim, K., Schinazi, R.F., Perilla, J.R., Kim, B., Kvaratskhelia, M.(2024) bioRxiv
- PubMed: 38328097
- DOI: https://doi.org/10.1101/2024.01.26.577387
- Primary Citation of Related Structures:
8D3S, 8S9Q, 8T52, 8T5A, 8T5B - PubMed Abstract:
Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are investigational antiretroviral agents which potently impair virion maturation by inducing hyper-multimerization of IN and inhibiting its interaction with viral genomic RNA. The pyrrolopyridine-based ALLINI pirmitegravir (PIR) has recently advanced into Phase 2a clinical trials. Previous cell culture based viral breakthrough assays identified the HIV-1 (Y99H/A128T IN) variant that confers substantial resistance to this inhibitor. Here, we have elucidated the unexpected mechanism of viral resistance to PIR. While both Tyr99 and Ala128 are positioned within the inhibitor binding V-shaped cavity at the IN catalytic core domain (CCD) dimer interface, the Y99H/A128T IN mutations did not substantially affect direct binding of PIR to the CCD dimer or functional oligomerization of full-length IN. Instead, the drug-resistant mutations introduced a steric hindrance at the inhibitor mediated interface between CCD and C-terminal domain (CTD) and compromised CTD binding to the CCD Y99H/A128T + PIR complex. Consequently, full-length IN Y99H/A128T was substantially less susceptible to the PIR induced hyper-multimerization than the WT protein, and HIV-1 (Y99H/A128T IN) conferred >150-fold resistance to the inhibitor compared to the WT virus. By rationally modifying PIR we have developed its analog EKC110, which readily induced hyper-multimerization of IN Y99H/A128T in vitro and was ~14-fold more potent against HIV-1 (Y99H/A128T IN) than the parent inhibitor. These findings suggest a path for developing improved PIR chemotypes with a higher barrier to resistance for their potential clinical use.
Organizational Affiliation:
Division of Infectious Diseases, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
