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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Bibliographic Details
Published in:PLoS pathogens Vol. 17; no. 7; p. e1009671
Main Authors: 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
Format: Journal Article
Language:English
Published: United States Public Library of Science 22.07.2021
Public Library of Science (PLoS)
Subjects:
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
Online Access:Get full text
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Summary: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.
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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