| Added by | alainmange |
|---|---|
| Group name | PlateformePP2I |
| Item Type | Journal Article |
| Title | A new class of capsid-targeting inhibitors that specifically block HIV-1 nuclear import |
| Creator | Boulay et al. |
| Author | Aude Boulay |
| Author | Emmanuel Quevarec |
| Author | Isabelle Malet |
| Author | Giuseppe Nicastro |
| Author | Célia Chamontin |
| Author | Suzon Perrin |
| Author | Corinne Henriquet |
| Author | Martine Pugnière |
| Author | Valérie Courgnaud |
| Author | Mickaël Blaise |
| Author | Anne-Geneviève Marcelin |
| Author | Ian A. Taylor |
| Author | Laurent Chaloin |
| Author | Nathalie J. Arhel |
| Abstract | HIV-1 capsids cross nuclear pore complexes (NPCs) by engaging with the nuclear import machinery. To identify compounds that inhibit HIV-1 nuclear import, we screened drugs in silico on a three-dimensional model of a CA hexamer bound by Transportin-1 (TRN-1). Among hits, compound H27 inhibited HIV-1 with a low micromolar IC50. Unlike other CA-targeting compounds, H27 did not alter CA assembly or disassembly, inhibited nuclear import specifically, and retained antiviral activity against PF74- and Lenacapavir-resistant mutants. The differential sensitivity of divergent primate lentiviral capsids, capsid stability and H27 escape mutants, together with structural analyses, suggest that H27 makes multiple low affinity contacts with assembled capsid. Interaction experiments indicate that H27 may act by preventing CA from engaging with components of the NPC machinery such as TRN-1. H27 exhibited good metabolic stability in vivo and was efficient against different subtypes and circulating recombinant forms from treatment-naïve patients as well as strains resistant to the four main classes of antiretroviral drugs. This work identifies compounds that demonstrate a novel mechanism of action by specifically blocking HIV-1 nuclear import. |
| Publication | EMBO molecular medicine |
| Volume | 16 |
| Issue | 11 |
| Pages | 2918-2945 |
| Date | 2024-11 |
| Journal Abbr | EMBO Mol Med |
| Language | eng |
| DOI | 10.1038/s44321-024-00143-w |
| ISSN | 1757-4684 |
| Library Catalog | PubMed |
| Extra | PMID: 39358603 PMCID: PMC11555092 |
| Tags | Active Transport, Cell Nucleus, Animals, Anti-HIV Agents, Antiretroviral Therapy, Capsid Proteins, Drug Discovery, Drug Evaluation, Preclinical, HIV Infections, HIV-1, Humans, Models, Molecular, Nuclear Import, original, pp2i |
| Date Added | 2024/12/03 - 10:37:42 |
| Date Modified | 2024/12/03 - 11:03:41 |
| Notes and Attachments | PubMed entry (Attachment) |
Institut de Recherche en Cancérologie de
