{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T09:21:28Z","timestamp":1763025688313,"version":"3.45.0"},"reference-count":79,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T00:00:00Z","timestamp":1762905600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["2R15AI062713-02","7R15AI062713-03","1R15AI152023-01A1"],"award-info":[{"award-number":["2R15AI062713-02","7R15AI062713-03","1R15AI152023-01A1"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Mercer University Seed Funds"},{"name":"Mercer University School of Medicine Biomedical Sciences Masters Program"},{"name":"Mercer Undergraduate Biomedical Scholar (MUBS) Training Initiative"},{"name":"University of Alabama Start-Up funds"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>The Varicella-zoster virus (VZV) open reading frame 54 (ORF54) gene encodes an 87 kDa monomer that oligomerizes to form the pORF54 portal dodecamer. Located at a single viral capsid vertex, the portal facilitates the translocation of the newly synthesized viral genome into the preformed empty capsid. Previously described \u03b1-methylbenzyl thiourea compounds were shown to inhibit VZV DNA encapsidation, likely by targeting pORF54. In this study, drug resistant isolates were obtained via passage of VZV in increasing concentrations of one analog, Compound I (Comp I). Mutations identified in four compound resistant isolates (amino acids 48, 304, 324 and 407) all localized to a region of the portal that was predicted to interface with capsid proteins. The portal is known to undergo significant conformational changes at the portal\u2013capsid interface during DNA encapsidation. A set of recombinant viruses was designed to reveal the chemical and physical importance of each of the resistance mutations at the portal\u2013capsid interface, the proposed binding site of the compound series. In addition, we employed a novel complementing cell line to show that despite the presence of the portal in the virion, DNA encapsidation did not occur. We propose that a-methylbenzyl thiourea compounds perturb interactions at or near the portal\u2013capsid interface and prevent conformational changes needed to support DNA encapsidation.<\/jats:p>","DOI":"10.3390\/v17111496","type":"journal-article","created":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T09:10:45Z","timestamp":1763025045000},"page":"1496","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Small Molecule Compounds Inhibit Varicella-Zoster Virus Replication by Targeting the Portal Protein\u2013Capsid Interface"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4934-5961","authenticated-orcid":false,"given":"Julius","family":"Svensmark","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31404, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily","family":"Polk","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31404, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ellyn","family":"Kornfeind","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31404, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Whitney","family":"Lane","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Purdue University-Fort Wayne, Fort Wayne, IN 46805, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melissa A.","family":"Visalli","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31404, USA"},{"name":"Department of Biological Sciences, Purdue University-Fort Wayne, Fort Wayne, IN 46805, USA"},{"name":"Department of Biological Sciences, University of Alabama, Tuscaloosa, AL 35487, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert J.","family":"Visalli","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31404, USA"},{"name":"Department of Biological Sciences, Purdue University-Fort Wayne, Fort Wayne, IN 46805, USA"},{"name":"Department of Biological Sciences, University of Alabama, Tuscaloosa, AL 35487, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Arvin, A., Campadelli-Fiume, G., Mocarski, E., Moore, P.S., and Roizman, B. 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