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The presence of a 3\u2032-to-5\u2032 proofreading exoribonuclease (ExoN) in coronaviruses diminishes the potency of many ribonucleotide analogs. The ability to interfere with ExoN activity will create new possibilities for control of SARS-CoV-2 infection. ExoN is formed by a 1:1 complex of nsp14 and nsp10 proteins. We have purified and characterized ExoN using a robust, quantitative system that reveals determinants of specificity and efficiency of hydrolysis. Double-stranded RNA is preferred over single-stranded RNA. Nucleotide excision is distributive, with only one or two nucleotides hydrolyzed in a single binding event. The composition of the terminal basepair modulates excision. A stalled SARS-CoV-2 replicase in complex with either correctly or incorrectly terminated products prevents excision, suggesting that a mispaired end is insufficient to displace the replicase. Finally, we have discovered several modifications to the 3\u2032-RNA terminus that interfere with or block ExoN-catalyzed excision. While a 3\u2032-OH facilitates hydrolysis of a nucleotide with a normal ribose configuration, this substituent is not required for a nucleotide with a planar ribose configuration such as that present in the antiviral nucleotide produced by viperin. Design of ExoN-resistant, antiviral ribonucleotides should be feasible.<\/jats:p>","DOI":"10.1093\/nar\/gkac1177","type":"journal-article","created":{"date-parts":[[2022,11,27]],"date-time":"2022-11-27T17:04:31Z","timestamp":1669568671000},"page":"315-336","source":"Crossref","is-referenced-by-count":27,"title":["Interfering with nucleotide excision by the coronavirus 3\u2032-to-5\u2032 exoribonuclease"],"prefix":"10.1093","volume":"51","author":[{"given":"Rukesh","family":"Chinthapatla","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill School of Medicine , Chapel Hill, NC 27599 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamad","family":"Sotoudegan","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill School of Medicine , Chapel Hill, NC 27599 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pankaj","family":"Srivastava","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill School of Medicine , Chapel Hill, NC 27599 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas K","family":"Anderson","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Institute for Molecular Virology, University of Wisconsin-Madison , Madison , WI 53706 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ibrahim\u00a0M","family":"Moustafa","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park , PA 16802 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kellan\u00a0T","family":"Passow","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, University of Minnesota , Minneapolis , MN 55455 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha\u00a0A","family":"Kennelly","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, University of Minnesota , Minneapolis , MN 55455 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramkumar","family":"Moorthy","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, University of Minnesota , Minneapolis , MN 55455 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Dulin","sequence":"additional","affiliation":[{"name":"Department of Physics and Astronomy, and LaserLaB Amsterdam, Vrije Universiteit Amsterdam , Amsterdam , The\u00a0 Netherlands"},{"name":"Junior Research Group 2, Interdisciplinary Center for Clinical Research, Friedrich-Alexander-University Erlangen-N\u00fcrnberg (FAU) , Cauerstr. 3, 91058 Erlangen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4837-1911","authenticated-orcid":false,"given":"Joy\u00a0Y","family":"Feng","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc , Foster City , CA 94404 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel\u00a0A","family":"Harki","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, University of Minnesota , Minneapolis , MN 55455 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert\u00a0N","family":"Kirchdoerfer","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Institute for Molecular Virology, University of Wisconsin-Madison , Madison , WI 53706 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7564-5642","authenticated-orcid":false,"given":"Craig\u00a0E","family":"Cameron","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill School of Medicine , Chapel Hill, NC 27599 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie\u00a0J","family":"Arnold","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill School of Medicine , Chapel Hill, NC 27599 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,12,22]]},"reference":[{"key":"2023011609414234200_B1","doi-asserted-by":"crossref","first-page":"1813","DOI":"10.1056\/NEJMoa2007764","article-title":"Remdesivir for the treatment of Covid-19 - Final report","volume":"383","author":"Beigel","year":"2020","journal-title":"N. 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