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HIV-1 Integrase catalytic core domain complexed with allosteric inhibitor STP03-0404HIV-1 Integrase catalytic core domain complexed with allosteric inhibitor STP03-0404
Structural highlights
Publication Abstract from PubMedAllosteric 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. A highly potent and safe pyrrolopyridine-based allosteric HIV-1 integrase inhibitor targeting host LEDGF/p75-integrase interaction site.,Maehigashi T, Ahn S, Kim UI, Lindenberger J, Oo A, Koneru PC, Mahboubi B, Engelman AN, Kvaratskhelia M, Kim K, Kim B PLoS Pathog. 2021 Jul 22;17(7):e1009671. doi: 10.1371/journal.ppat.1009671., eCollection 2021 Jul. PMID:34293041[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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