Authors
Nidhi Sharma, Xiaoyun Xie, Renata Szczepaniak, Chitra Rani, Sheida Khojasteh Khosro, Jolanta Krucinska, Xiaoling Chen, Dung Do, Lee Wright, Dennis Wright, Sandra Weller
Published in
PLoS pathogens. Volume 22. Issue 8. Pages e1014531. Aug 17, 2026. Epub Aug 17, 2026.
Abstract
Herpes simplex virus 1 (HSV-1) UL12 encodes a highly conserved 5' → 3' alkaline exonuclease that is essential for the production of infectious virus. Together with the viral single-stranded DNA-binding/annealing protein ICP8, UL12 functions as a two-component recombinase that mediates recombination-dependent viral DNA replication. Here, we present the crystal structure of the catalytic domain of the HSV alkaline nuclease (UL12), which provides the first view of an α-herpesvirus alkaline nuclease. Using this structure, we optimized a series of small-molecule viral nuclease inhibitors (VNIs) that target the UL12 active site and potently inhibit UL12 exonuclease activity in vitro. We have thus established a robust platform for structure-based docking, SAR analysis and rational inhibitor design. Because UL12 orthologs are conserved across all human herpesviruses, we examined the activity of these compounds against the β- and γ-herpesvirus alkaline nucleases UL98 and SOX and found that they inhibit all three enzymes. The VNIs also exhibit antiviral activity against HSV-1 and HCMV in cell culture. EC50 and IC50 values were in the nanomolar to low micromolar range. Together, these findings establish herpesvirus alkaline nucleases as conserved, druggable antiviral targets and provide a foundation for the development of broad-spectrum anti-herpesvirus therapeutics, either as standalone agents or in combination with existing nucleoside analogs.
PMID:
42607086
Bibliographic data and abstract were imported from PubMed on 18 Aug 2026.
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