Structural, biophysical, and virological mechanistic characterization of HIV-1 capsid-targeting antivirals

2025 · doi:10.64898/2025.12.30.696960
preprint OA: closed CC-BY-NC-ND-4.0
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⚙ AI-generated deep summary by claude@2026-07, 2026-07-03 · read from full text ⓘ

The paper investigates HIV-1 capsid–targeting antivirals, focusing on whether chemical modifications to the PF74 scaffold at specific sites (R1 and R3) can improve antiviral performance. Using a cumulative set of structural, biophysical, and virological experiments, the authors report that the modified compounds show increased antiviral potency, enhanced stability of wild-type HIV capsid hexamers and virions, and tighter binding to wild-type capsid hexamers than PF74, along with altered interactions at the capsid “FG” binding site. The study frames PF74 as having been discontinued previously due to potency and metabolic issues, and positions these findings as mechanistic guidance for future clinical-use capsid-targeting antivirals, though no endometriosis- or adenomyosis-related limitation is stated. The paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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Abstract

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.
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Abstract 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. Competing Interest Statement The authors have declared no competing interest. Footnotes Author list has been updated to include Anastasia Selyutina.

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License: CC-BY-NC-ND-4.0