{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:19:20Z","timestamp":1785403160804,"version":"3.56.0"},"posted":{"date-parts":[[2026,6,25]]},"group-title":"Pharmacology and Toxicology","reference-count":33,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T00:00:00Z","timestamp":1782345600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"https:\/\/ror.org\/006w34k90","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Targeting viral macrodomains (Mac) has emerged as a promising strategy for antiviral drug development, especially after the outbreak of COVID-19 that claimed millions of lives worldwide. Several severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Mac1 inhibitors have been reported in the past few years. In the present work, we converted GS-441524 (IC\n                  <jats:sub>50<\/jats:sub>\n                  of \u223c10 \u03bcM for SARS-CoV-2 Mac1) to KP-S54 (\n                  <jats:bold>18c<\/jats:bold>\n                  ), a potent inhibitor of both SARS-CoV-2 Mac1 (IC\n                  <jats:sub>50<\/jats:sub>\n                  : 44 nM) and Middle East respiratory syndrome coronavirus (MERS-CoV) Mac1 (IC\n                  <jats:sub>50<\/jats:sub>\n                  : 91 nM) through an iterative direct-to-biology approach. This approach leverages efficient amide-coupling reaction and the mix-and-read fluorescence polarization (FP) assays where reaction mixtures could be screened directly without purification. Cocrystal structure of a selected derivative (\n                  <jats:bold>12p<\/jats:bold>\n                  ) binding to SARS-CoV-2 Mac1 revealed the binding mode, which will guide future drug development against viral macrodomains.\n                <\/jats:p>","DOI":"10.64898\/2026.06.24.734322","type":"posted-content","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T05:30:32Z","timestamp":1782451832000},"source":"Crossref","is-referenced-by-count":0,"title":["Development of GS-441524 Derivatives as Potent SARS-CoV-2 Mac1 Inhibitors via a Direct-to-Biology Approach"],"prefix":"10.64898","author":[{"given":"Kewen","family":"Peng","sequence":"first","affiliation":[{"name":"Department of Medicine, The University of Chicago, Chicago, IL 60637, USA"},{"name":"Center for Chemical Biology and Therapeutics, The University of Chicago, Chicago, IL 60637, USA"},{"name":"Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suryadeep","family":"Chakraborty","sequence":"additional","affiliation":[{"name":"Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shamar D.","family":"Wallace","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica Caroline Gomes","family":"Noll","sequence":"additional","affiliation":[{"name":"Departments of Microbiology & Immunology, Cornell University College of Veterinary Medicine, Ithaca NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jialin","family":"Shang","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Medicine, The University of Chicago, Chicago, IL 60637, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annette","family":"Choi","sequence":"additional","affiliation":[{"name":"Departments of Microbiology & Immunology, Cornell University College of Veterinary Medicine, Ithaca NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary","family":"Whittaker","sequence":"additional","affiliation":[{"name":"Departments of Microbiology & Immunology, Cornell University College of Veterinary Medicine, Ithaca NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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