{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T05:07:51Z","timestamp":1789016871190,"version":"build-2803163510"},"reference-count":210,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T00:00:00Z","timestamp":1788307200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Viral proteases process viral polyproteins into functional proteins and are therefore essential for viral replication and antiviral drug development. Most research has focused on mature enzymes, whereas precursor and partially processed protease forms remain poorly understood. This review examines viral protease maturation as a dynamic and temporally regulated process. Immature precursors are often membrane-associated and conformationally heterogeneous, and their activation is controlled by mechanisms such as cis cleavage, dimerization, cofactor binding, and interdomain communication. These regulatory steps represent potential vulnerabilities in production of viral progeny. We discuss how conformational dynamics influence protease maturation in coronaviruses, flaviviruses, picornaviruses, and retroviruses, and how defined precursor states may be pharmacologically exploited. Targeting these states could complement inhibition of the mature enzyme, increase the barrier to drug resistance, or dysregulate maturation by inducing premature protease activation, thereby disrupting viral particle production. Protease maturation therefore offers a conceptual framework for antiviral strategies that extend beyond classical active-site inhibition.<\/jats:p>","DOI":"10.3390\/v18090967","type":"journal-article","created":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T15:39:47Z","timestamp":1788363587000},"page":"967","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Conformational Dynamics of Viral Protease Precursors in Maturation, Inhibition, and Drug-Resistance Development"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5536-3587","authenticated-orcid":false,"given":"Ta\u0165\u00e1na","family":"Majerov\u00e1","sequence":"first","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, 166 10 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7325-6961","authenticated-orcid":false,"given":"Pavel","family":"Novotn\u00fd","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, 166 10 Prague, Czech Republic"},{"name":"Department of Physical and Macromolecular Chemistry, Faculty of Science, Charles University in Prague, 128 43 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Majerov\u00e1, T., and Novotn\u00fd, P. 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