Structural, biophysical, and virological mechanistic characterization of HIV-1 capsid-targeting antivirals
Due to its significant role in virus replication, the HIV capsid is an attractive antiviral target. This is validated by the recent clinical approval of lenacapavir for both treatment and pre-exposure prophylaxis (PrEP). PF74 is a well-characterized capsid-targeting antiviral that was discontinued in further study due to potency and metabolic issues. We hypothesized that making chemical modifications at certain sites of PF74 could result in capsid-targeting antivirals with improved potency and bioavailability. Our cumulative studies show that making changes at the R1 and R3 positions of PF74 results in compounds with increased antiviral potency, increased stability of wild-type HIV capsid hexamers and virions, tighter binding to wild-type HIV capsid hexamer compared to PF74, and different interactions at the "FG" binding site of capsid compared to PF74. These data provide insights into the design of future capsid-targeting antivirals relevant for clinical use.
Authors
- Maria E. Cilento (ORCID: https://orcid.org/0000-0001-7597-1248)
- Alexa A. Snyder (ORCID: https://orcid.org/0000-0001-9326-343X)
- Karen A. Kirby (ORCID: https://orcid.org/0000-0003-2468-4796)
- Charlotte Luchsinger (ORCID: https://orcid.org/0000-0001-6775-7778)
- Atsuko Hachiya
- Ashwanth C. Francis (ORCID: https://orcid.org/0000-0002-8663-2038)
- Zachary C. Lorson (ORCID: https://orcid.org/0009-0002-1404-9086)
- Andres Emanuelli Castaner (ORCID: https://orcid.org/0009-0005-1275-9684)
- Philip R. Tedbury (ORCID: https://orcid.org/0000-0001-8151-4967)
- W. McFadden
- Hu Zhang (ORCID: https://orcid.org/0000-0002-7447-8360)
- Gregory B. Melikyan (ORCID: https://orcid.org/0000-0001-5385-3013)
- S Ravichandran (ORCID: https://orcid.org/0009-0007-4960-3194)
- Stefan G. Sarafianos (ORCID: https://orcid.org/0000-0001-8151-4967)
- Zhengqiang Wang
- Xinyong Cai
- Arvin Nafisi
- Haijuan Du
- Lei Wang
- PhD Felipe R Diaz-Griffero
Institutions
- Florida State University (US)
- Albert Einstein College of Medicine (US)
- University of Minnesota (US)
- National Hospital Organization (JP)
- Children's Healthcare of Atlanta (US)
- Nagoya Medical Center (JP)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2025-12-31
- DOI
- https://doi.org/10.64898/2025.12.30.696960
- Citations
- 1
- Primary Topic
- HIV/AIDS drug development and treatment
- Type
- article
- Field-Weighted Citation Impact
- 1.40
Funders
- U.S. Department of Energy
- National Institutes of Health
- Office of Science
- National Institute of Allergy and Infectious Diseases
- Argonne National Laboratory