{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T18:23:04Z","timestamp":1787854984303,"version":"build-2784847793"},"update-to":[{"DOI":"10.1371\/journal.ppat.1014531","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000}}],"reference-count":74,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T00:00:00Z","timestamp":1786924800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI069136"],"award-info":[{"award-number":["AI069136"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R21 AI143272"],"award-info":[{"award-number":["R21 AI143272"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R56 AI173955"],"award-info":[{"award-number":["R56 AI173955"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["5R01AI021747-35"],"award-info":[{"award-number":["5R01AI021747-35"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Herpes simplex virus 1 (HSV-1) UL12 encodes a highly conserved 5\u2032\u2009\u2192\u20093\u2032 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 \u03b1-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 \u03b2- and \u03b3-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. EC\n                    <jats:sub>50<\/jats:sub>\n                    and IC\n                    <jats:sub>50<\/jats:sub>\n                    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.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1014531","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T17:34:03Z","timestamp":1786988043000},"page":"e1014531","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Viral Nuclease Inhibitors: Small molecule disruptors of the UL12 alkaline nuclease display broad anti-herpes virus activity"],"prefix":"10.1371","volume":"22","author":[{"given":"Nidhi","family":"Sharma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyun","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renata","family":"Szczepaniak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chitra","family":"Rani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheida Khojasteh","family":"Khosro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jolanta","family":"Krucinska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoling","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dung","family":"Do","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee","family":"Wright","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis","family":"Wright","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4519-6276","authenticated-orcid":true,"given":"Sandra","family":"Weller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,8,17]]},"reference":[{"key":"ppat.1014531.ref001","unstructured":"World Health Organization WHO. 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Human cytomegalovirus and transplantation: drug development and regulatory issues. 2016.","DOI":"10.1016\/S2055-6640(20)30457-X"},{"key":"ppat.1014531.ref011","doi-asserted-by":"crossref","unstructured":"Van Der Wekken-Pas LC, Tott\u00e9 J, Lunel FV, Van Zuilen A, Van Luin M. 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