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RNA-dependent RNA polymerase (RdRp) plays a critical role in the genome replication of RNA viruses and shows high structural conservation. No homologous protein exists in human cells, making RdRp an effective, safe, and broad-spectrum antiviral target. Therefore, establishing an RdRp activity assay for drug development based on its mechanism is of great significance. This paper summarizes the structural characteristics of RdRp and the methods for constructing RdRp activity assay, especially for cell-free activity assay. In addition, several reported RdRp inhibitors and their pharmaceutical progress are also reviewed, aiming to provide a reference for the development of novel antiviral drugs targeting RdRp.<\/jats:p>","DOI":"10.3390\/molecules31122044","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T12:14:58Z","timestamp":1781180098000},"page":"2044","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Positive-Strand RNA Viral RdRps: From Structure Conservation and Activity Assay to Drug Development"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-5759-1456","authenticated-orcid":false,"given":"Siyuan","family":"Zhao","sequence":"first","affiliation":[{"name":"College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyu","family":"Lin","sequence":"additional","affiliation":[{"name":"College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9378-3881","authenticated-orcid":false,"given":"Minglian","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.cell.2020.05.034","article-title":"Structural Basis for RNA Replication by the SARS-CoV-2 Polymerase","volume":"182","author":"Wang","year":"2020","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1016\/j.tim.2018.04.004","article-title":"Drug Repurposing for Viral Infectious Diseases: How Far Are We?","volume":"26","author":"Mercorelli","year":"2018","journal-title":"Trends Microbiol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Picarazzi, F., Vicenti, I., Saladini, F., Zazzi, M., and Mori, M. 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