A highly potent and safe pyrrolopyridine-based allosteric HIV-1 integrase inhibitor targeting host LEDGF/p75-integrase interaction site

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...

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Vydáno v:	PLoS pathogens Ročník 17; číslo 7; s. e1009671
Hlavní autoři:	Maehigashi, Tatsuya, Ahn, Seohyun, Kim, Uk-Il, Lindenberger, Jared, Oo, Adrian, Koneru, Pratibha C., Mahboubi, Bijan, Engelman, Alan N., Kvaratskhelia, Mamuka, Kim, Kyungjin, Kim, Baek
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Public Library of Science 22.07.2021 Public Library of Science (PLoS)
Témata:	Allosteric properties Allosteric Regulation - drug effects Animals Anti-HIV agents Antiviral agents Binding sites Biocompatibility Biology and Life Sciences Clinical trials Cloning Cytotoxicity Dimers Dogs Drug therapy Genomes Health aspects Heterocyclic aromatic compounds HIV HIV infection HIV Infections - drug therapy HIV Integrase Inhibitors - pharmacology HIV-1 - drug effects Human immunodeficiency virus Humans In vivo methods and tests Integrase Integrase inhibitors Intercellular Signaling Peptides and Proteins - metabolism Localization Maturation Medicine and Health Sciences Mutation Oligomerization p75 Protein Pharmaceutical research Pyrrolopyridines Rats Rats, Sprague-Dawley Research and analysis methods Ribonucleic acid RNA Standard deviation Toxicity Virus Replication - drug effects Viruses United States
ISSN:	1553-7374, 1553-7366, 1553-7374
On-line přístup:	Získat plný text
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Popis
Shrnutí:	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 IC 50 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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 I have read the journal’s policy and the authors of this manuscript have the following competing interests: S.A., U.K., and K.K. are employees of ST Pharm, B.K. is consultant of ST Pharm, and A.N.E. consults for ViiV Healthcare, Co.. All other authors declare no competing interests.
ISSN:	1553-7374 1553-7366 1553-7374
DOI:	10.1371/journal.ppat.1009671