---
title: "Allosteric capsid inhibitors (allosteres) alter HIV-1 capsid structure and trigger cGAS-dependent"
id: "biorxiv-7-allosteric-capsid-inhibitors-and-their-escape-mutants-drive-hiv-1-sensing"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-7-allosteric-capsid-inhibitors-and-their-escape-mutants-drive-hiv-1-sensing"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.08.21.746246v1?rss=1"
published_at: "2026-08-26T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Allosteric capsid inhibitors (allosteres) alter HIV-1 capsid structure and trigger cGAS-dependent
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-7-allosteric-capsid-inhibitors-and-their-escape-mutants-drive-hiv-1-sensing
- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.08.21.746246v1?rss=1)
- **Published At:** 2026-08-26T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- Researchers designed small-molecule **allosteric** capsid inhibitors (termed “allosteres”) that bind the HIV-1 capsid pocket normally engaged by FG motif-bearing host cofactors (Sec24C, NUP153, CPSF6 and disordered nucleoporins in the nuclear pore central channel). - X-ray crystal structures of capsid–inhibitor complexes show that inhibitor binding produces allosteric shifts in the capsid C‑terminal domain, altering the capsid lattice around the three‑fold symmetry axis. - The structural perturbations are consistent with an **uncoating** mechanism: treatment with allosteres causes HIV-1 to trigger an innate immune response dependent on viral DNA and the DNA sensor **cGAS**. - Allosteres lose potency against clinically relevant **Lenacapavir** resistance mutants, mirroring cross-resistance observed with other capsid-targeting compounds. - Strikingly, HIV-1 bearing key resistance mutations stimulates innate immune activation even in the absence of inhibitor, indicating that some escape variants have intrinsic instability or altered uncoating that exposes viral DNA to sensing. - The authors propose that increased sensitivity of resistant mutants to **cGAS** may contribute to reduced HIV-1 transmission during Lenacapavir use in prophylaxis. - The work broadens the chemical scaffold space for HIV capsid inhibitors, supplies mechanistic detail linking capsid binding to lattice changes and immune sensing, and aims to inform improved inhibitor design. - Specific experimental methods, quantitative potency values, detailed resistance mutations, and in vivo data were not reported in the source abstract and would be found in the full manuscript.
## Clinical Analysis & Structured Key Points
Allosteric capsid inhibitors and their escape mutants drive HIV-1 sensing | bioRxiv Skip to main content New Results Allosteric capsid inhibitors and their escape mutants drive HIV-1 sensing View ORCID Profile Kate L Morling , Morton L Govasli , Ben Graham , Justin Warne , Lauren Harrison , Lucy G Thorne , View ORCID Profile Lydia S Newton , Joshua Maw , Emma Touizer , Rebecca P Sumner , Sally Oxenford , Joanna Rowley , Dara Annett , View ORCID Profile David Jacques , View ORCID Profile Till Boecking , View ORCID Profile Nikos Pinotsis , View ORCID Profile David Lawrence Selwood , View ORCID Profile Greg J Towers doi: https://doi.org/10.64898/2026.08.21.746246 Kate L Morling 1 University of Cambridge; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Kate L Morling Morton L Govasli 2 University of Bergen; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Ben Graham 3 University College London; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Justin Warne 4 The Institute of Cancer Research; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Lauren Harrison 3 University College London; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Lucy G Thorne 5 Imperial College London; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Lydia S Newton 5 Imperial College London; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Lydia S Newton Joshua Maw 3 University College London; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Emma Touizer 5 Imperial College London; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Rebecca P Sumner 6 University of Surrey; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Sally Oxenford 3 University College London; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Joanna Rowley 3 University College London; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Dara Annett 7 Queen Mary University of London; Find this author on Google Scholar Find this author on PubMed Search for this author on this site David Jacques 8 University of New South Wales; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for David Jacques Till Boecking 8 University of New South Wales; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Till Boecking Nikos Pinotsis 9 Birkbeck College Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Nikos Pinotsis David Lawrence Selwood 3 University College London; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for David Lawrence Selwood Greg J Towers 7 Queen Mary University of London; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Greg J Towers For correspondence: g.towers{at}qmul.ac.uk Abstract Info/History Metrics Preview PDF Abstract Small-molecule capsid inhibitors suppress HIV-1 infectivity by binding to capsid at the same site as FG motif-bearing host cofactors Sec24C, NUP153, CPSF6 and disordered nucleoporins residing in the nuclear pore complex central channel. We have used rational design to develop inhibitors called "allosteres" that target this pocket and inhibit HIV-1 infectivity. X-ray crystal structures of capsid/inhibitor complexes, reveal allosteric shifts upon inhibitor binding in the capsid C-terminal domain which impact the capsid lattice three-fold symmetry axis. Consistent with an uncoating mechanism, we find that allosteres cause HIV-1 to trigger innate immune response dependent on viral DNA and DNA sensor cGAS. Allosteres exhibit a similar loss of potency against clinically induced Lenacapavir resistance mutants but, strikingly, we find that HIV-1 bearing key resistance mutations induces innate immune activation in the absence of inhibitor. We hypothesise that resistant mutant sensitivity to cGAS contributes to reduction of HIV-1 transmission during Lenacapavir use in prophylaxis. Our work expands the physicochemical space and scaffold range for HIV capsid targeting inhibitors, provides mechanistic details of inhibition and facilitates improved inhibitor design. Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . Back to top Previous Next Posted August 26, 2026. Download PDF Email Thank you for your interest in spreading the word about bioRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following Allosteric capsid inhibitors and their escape mutants drive HIV-1 sensing Message Subject (Your Name) has forwarded a page to you from bioRxiv Message Body (Your Name) thought you would like to see this page from the bioRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Share Allosteric capsid inhibitors and their escape mutants drive HIV-1 sensing Kate L Morling , Morton L Govasli , Ben Graham , Justin Warne , Lauren Harrison , Lucy G Thorne , Lydia S Newton , Joshua Maw , Emma Touizer , Rebecca P Sumner , Sally Oxenford , Joanna Rowley , Dara Annett , David Jacques , Till Boecking , Nikos Pinotsis , David Lawrence Selwood , Greg J Towers bioRxiv 2026.08.21.746246; doi: https://doi.org/10.64898/2026.08.21.746246 Share This Article: Copy Citation Tools Allosteric capsid inhibitors and their escape mutants drive HIV-1 sensing Kate L Morling , Morton L Govasli , Ben Graham , Justin Warne , Lauren Harrison , Lucy G Thorne , Lydia S Newton , Joshua Maw , Emma Touizer , Rebecca P Sumner , Sally Oxenford , Joanna Rowley , Dara Annett , David Jacques , Till Boecking , Nikos Pinotsis , David Lawrence Selwood , Greg J Towers bioRxiv 2026.08.21.746246; doi: https://doi.org/10.64898/2026.08.21.746246 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Areas All Articles Animal Behavior and Cognition (7932) Biochemistry (18539) Bioengineering (14701) Bioinformatics (43919) Biophysics (22341) Cancer Biology (19465) Cell Biology (26636) Clinical Trials (138) Developmental Biology (13845) Ecology (20770) Epidemiology (2067) Evolutionary Biology (25202) Genetics (16047) Genomics (23311) Immunology (18502) Microbiology (42025) Molecular Biology (17860) Neuroscience (92421) Paleontology (691) Pathology (2953) Pharmacology and Toxicology (5045) Physiology (8025) Plant Biology (15814) Scientific Communication and Education (2089) Synthetic Biology (4517) Systems Biology (10146) Zoology (2367)
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