| Title: |
Biological and Structural Analyses of New Potent Allosteric Inhibitors of HIV-1 Integrase |
| Authors: |
Bonnard, Damien; Le Rouzic, Erwann; Singer, Matthew; Yu, Zhe; Le Strat, Frédéric; Batisse, Claire; Batisse, Julien; Amadori, Céline; Chasset, Sophie; Pye, Valerie; Emiliani, Stéphane; Ledoussal, Benoit; Ruff, Marc; Moreau, François; Cherepanov, Peter; Benarous, Richard |
| Contributors: |
Institut de génétique et biologie moléculaire et cellulaire (IGBMC); Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS); Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC); Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS); ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010); ANR-20-SFRI-0012,STRAT'US,Façonner les talents en formation et en recherche à l'Université de Strasbourg(2020); ANR-17-EURE-0023,IMCBio,Integrative Molecular and Cellular Biology(2017); ANR-10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010); European Project: 305137,FP7-HEALTH-2012-INNOVATION-1,FP7-HEALTH-2012-INNOVATION-1,HIVINNOV(2012) |
| Source: |
ISSN: 0066-4804. |
| Publisher Information: |
CCSD; American Society for Microbiology |
| Publication Year: |
2023 |
| Subject Terms: |
[SDV.BBM]Life Sciences [q-bio]/Biochemistry; Molecular Biology |
| Description: |
HIV-1 integrase-LEDGF allosteric inhibitors (INLAIs) share the binding site on the viral protein with the host factor LEDGF/p75. These small molecules act as molecular glues promoting hyper-multimerization of HIV-1 IN protein to severely perturb maturation of viral particles. Herein, we describe a new series of INLAIs based on a benzene scaffold that display antiviral activity in the single digit nanomolar range. Akin to other compounds of this class, the INLAIs predominantly inhibit the late stages of HIV-1 replication. A series of high-resolution crystal structures revealed how these small molecules engage the catalytic core and the C-terminal domains of HIV-1 IN. No antagonism was observed between our lead INLAI compound BDM-2 and a panel of 16 clinical antiretrovirals. Moreover, we show that compounds retained high antiviral activity against HIV-1 variants resistant to IN strand transfer inhibitors and other classes of antiretroviral drugs. The virologic profile of BDM-2 and the recently completed single ascending dose phase I trial (ClinicalTrials.gov identifier: NCT03634085) warrant further clinical investigation for use in combination with other antiretroviral drugs. Moreover, our results suggest routes for further improvement of this emerging drug class. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
info:eu-repo/grantAgreement//305137/EU/Generation of a new class of antiretrovirals targeting HIV-cellular cofactors interactions/HIVINNOV |
| DOI: |
10.1128/aac.00462-23 |
| Availability: |
https://hal.science/hal-04219166; https://hal.science/hal-04219166v1/document; https://hal.science/hal-04219166v1/file/islandora_167400.pdf; https://doi.org/10.1128/aac.00462-23 |
| Rights: |
https://about.hal.science/hal-authorisation-v1/ ; info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.BBED7731 |
| Database: |
BASE |