{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T02:13:41Z","timestamp":1791857621024,"version":"4.3.4"},"posted":{"date-parts":[[2025,10,14]]},"group-title":"Pharmacology and Toxicology","reference-count":27,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T00:00:00Z","timestamp":1760400000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["U19AI171110"],"award-info":[{"award-number":["U19AI171110"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,14]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  The COVID-19 pandemic made plain the need for effective antivirals acting on novel antiviral targets, among which viral macrodomains have attracted considerable attention. We recently described AVI-4206 (\n                  <jats:bold>1<\/jats:bold>\n                  ), a potent and selective inhibitor of the SARS-CoV-2 ADP-ribosylhydrolase Mac1 based on a 9\n                  <jats:italic>H<\/jats:italic>\n                  -pyrimido[4,5-\n                  <jats:italic>b<\/jats:italic>\n                  ]indole core, the first Mac1 inhibitor to demonstrate antiviral efficacy in mouse models of SARS-CoV-2 infection, but requiring IP administration and frequent dosing. Herein we describe an extensive, structurally enabled medicinal chemistry effort to identify orally bioavailable Mac1 inhibitors by addressing permeability and efflux liabilities of\n                  <jats:bold>1<\/jats:bold>\n                  and many of its analogs. Multiple strategies were pursued to overcome these issues, including replacing a urea function to reduce hydrogen bond donor count. While heterocyclic urea mimetics could deliver analogs like AVI-6318 (\n                  <jats:bold>3<\/jats:bold>\n                  ) with potencies and ADME profiles similar to\n                  <jats:bold>1<\/jats:bold>\n                  , abrogation of the P-gp liability was finally achieved with entirely non-polar substituents in place of urea. Thus, AVI-6451 (\n                  <jats:bold>4<\/jats:bold>\n                  ) is a potent Mac1 inhibitor lead with low intrinsic clearance, high oral bioavailability, and antiviral efficacy with once-daily oral administration in a mouse model of SARS-CoV-2 infection.\n                <\/jats:p>","DOI":"10.1101\/2025.10.11.681833","type":"posted-content","created":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T23:00:14Z","timestamp":1760482814000},"source":"Crossref","is-referenced-by-count":5,"title":["Discovery of AVI-6451, a Potent and Selective Inhibitor of the SARS-CoV-2 ADP-Ribosylhydrolase Mac1 with Oral Efficacy in vivo"],"prefix":"10.64898","author":[{"given":"Priyadarshini","family":"Jaishankar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Galen J.","family":"Correy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Matsui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takaya","family":"Togo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moira M.","family":"Rachman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maisie G.V.","family":"Stevens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric R.","family":"Hantz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morgan E.","family":"Diolaiti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauricio","family":"Montano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taha Y.","family":"Taha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Rosecrans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julius","family":"Pampel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nevan J.","family":"Krogan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian K.","family":"Shoichet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Ashworth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Ott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5080-2859","authenticated-orcid":false,"given":"James S.","family":"Fraser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1240-2846","authenticated-orcid":false,"given":"Adam R.","family":"Renslo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025101614201455000_2025.10.11.681833v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-023-00672-y"},{"key":"2025101614201455000_2025.10.11.681833v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-023-00692-8"},{"key":"2025101614201455000_2025.10.11.681833v1.3","doi-asserted-by":"crossref","unstructured":"Leung, A. 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