Download MendeleyA highly potent and safe pyrrolopyridine-based allosteric HIV-1 integrase inhibitor targeting host LEDGF/p75-integrase interaction site.
Maehigashi, T., Ahn, S., Kim, U.I., Lindenberger, J., Oo, A., Koneru, P.C., Mahboubi, B., Engelman, A.N., Kvaratskhelia, M., Kim, K., Kim, B.(2021) PLoS Pathog 17: e1009671-e1009671
- PubMed: 34293041
- DOI: https://doi.org/10.1371/journal.ppat.1009671
- Primary Citation of Related Structures:
7KE0 - PubMed Abstract:
Allosteric integrase inhibitors (ALLINIs) are a class of experimental anti-HIV agents that target the noncatalytic sites of the viral integrase (IN) and interfere with the IN-viral RNA interaction during viral maturation. Here, we report a highly potent and safe pyrrolopyridine-based ALLINI, STP0404, displaying picomolar IC50 in human PBMCs with a >24,000 therapeutic index against HIV-1. X-ray structural and biochemical analyses revealed that STP0404 binds to the host LEDGF/p75 protein binding pocket of the IN dimer, which induces aberrant IN oligomerization and blocks the IN-RNA interaction. Consequently, STP0404 inhibits proper localization of HIV-1 RNA genomes in viral particles during viral maturation. Y99H and A128T mutations at the LEDGF/p75 binding pocket render resistance to STP0404. Extensive in vivo pharmacological and toxicity investigations demonstrate that STP0404 harbors outstanding therapeutic and safety properties. Overall, STP0404 is a potent and first-in-class ALLINI that targets LEDGF/p75 binding site and has advanced to a human trial.
Organizational Affiliation:
Department of Pediatrics, School of Medicine, Emory University, Atlanta, Georgia, United States of America.
