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CoVs encode for a macrodomain (Mac1) that binds to and removes ADP-ribose from target proteins. SARS-CoV-2 Mac1 promotes virus replication in the presence of interferon (IFN) and blocks the production of IFN, although the mechanisms by which it mediates these functions remain unknown. Mac1 inhibitors could help elucidate these mechanisms and serve as therapeutic agents against CoV-induced diseases. We previously identified compound\n                      <jats:bold>4a<\/jats:bold>\n                      (a.k.a. MCD-628), a pyrrolo-pyrimidine that inhibited Mac1 activity\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      at low micromolar levels. Here, we determined the binding mode of\n                      <jats:bold>4a<\/jats:bold>\n                      by crystallography, further defining its interaction with Mac1. However,\n                      <jats:bold>4a<\/jats:bold>\n                      did not reduce CoV replication, which we hypothesized was due to its acidic side chain limiting permeability. To test this hypothesis, we developed several hydrophobic derivatives of\n                      <jats:bold>4a<\/jats:bold>\n                      . We identified four compounds that both inhibited Mac1\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      and inhibited murine hepatitis virus (MHV) replication:\n                      <jats:bold>5a<\/jats:bold>\n                      ,\n                      <jats:bold>5c<\/jats:bold>\n                      ,\n                      <jats:bold>6d<\/jats:bold>\n                      , and\n                      <jats:bold>6e<\/jats:bold>\n                      . Furthermore,\n                      <jats:bold>5c<\/jats:bold>\n                      and\n                      <jats:bold>6e<\/jats:bold>\n                      inhibited SARS-CoV-2 replication only in the presence of IFN\u03b3, similar to a Mac1 deletion virus. To confirm their specificity, we passed MHV in the presence of\n                      <jats:bold>5a<\/jats:bold>\n                      to identify drug-resistant mutations and identified an alanine-to-threonine and glycine-to-valine double mutation in Mac1. Recombinant virus with these mutations had enhanced replication compared with the WT virus when treated with\n                      <jats:bold>5a<\/jats:bold>\n                      , demonstrating the specificity of these compounds during infection. However, this virus is highly attenuated\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      , indicating that drug resistance emerged at the expense of viral fitness.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>Coronaviruses (CoVs) present significant threats to human and animal health, as evidenced by recent outbreaks of MERS-CoV and SARS-CoV-2. CoVs encode for a highly conserved macrodomain protein (Mac1) that binds to and removes ADP-ribose from proteins, which promotes virus replication and blocks IFN production, although the exact mechanisms remain unclear. Inhibiting Mac1 could provide valuable insights into these mechanisms and offer new therapeutic avenues for CoV-induced diseases. We have identified several unique pyrrolo-pyrimidine-based compounds as Mac1 inhibitors. Notably, at least two of these compounds inhibited both murine hepatitis virus (MHV) and SARS-CoV-2 replication. Furthermore, we identified a drug-resistant mutation in Mac1, confirming target specificity during infection. However, this mutant is highly attenuated in mice, indicating that drug resistance appears to come at a fitness cost. These results emphasize the potential of Mac1 as a drug target and the promise of structure-based inhibitor design in combating CoV infections.<\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.03865-24","type":"journal-article","created":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T09:00:53Z","timestamp":1747990853000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":15,"title":["Identification of a series of pyrrolo-pyrimidine-based SARS-CoV-2 Mac1 inhibitors that repress coronavirus replication"],"prefix":"10.1128","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-0783-3208","authenticated-orcid":false,"given":"Jessica J.","family":"Pfannenstiel","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/001tmjg57","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Molecular Biosciences, University of 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