{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T15:53:48Z","timestamp":1790351628101,"version":"4.1.0"},"reference-count":59,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2024,2,2]],"date-time":"2024-02-02T00:00:00Z","timestamp":1706832000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Laboratory of Virology","award":["RRF-2.3.1-21-2022-00010"],"award-info":[{"award-number":["RRF-2.3.1-21-2022-00010"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has presented an enormous challenge to health care systems and medicine. As a result of global research efforts aimed at preventing and effectively treating SARS-CoV-2 infection, vaccines with fundamentally new mechanisms of action and some small-molecule antiviral drugs targeting key proteins in the viral cycle have been developed. The most effective small-molecule drug approved to date for the treatment of COVID-19 is PaxlovidTM, which is a combination of two protease inhibitors, nirmatrelvir and ritonavir. Nirmatrelvir is a reversible covalent peptidomimetic inhibitor of the main protease (Mpro) of SARS-CoV-2, which enzyme plays a crucial role in viral reproduction. In this combination, ritonavir serves as a pharmacokinetic enhancer, it irreversibly inhibits the cytochrome CYP3A4 enzyme responsible for the rapid metabolism of nirmatrelvir, thereby increasing the half-life and bioavailability of nirmatrelvir. In this tutorial review, we summarize the development and pharmaceutical chemistry aspects of Paxlovid, covering the evolution of protease inhibitors, the warhead design, synthesis and the mechanism of action of nirmatrelvir, as well as the synthesis of ritonavir and its CYP3A4 inhibition mechanism. The efficacy of Paxlovid to novel virus mutants is also overviewed.<\/jats:p>","DOI":"10.3390\/pharmaceutics16020217","type":"journal-article","created":{"date-parts":[[2024,2,2]],"date-time":"2024-02-02T09:24:08Z","timestamp":1706865848000},"page":"217","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["The Design, Synthesis and Mechanism of Action of Paxlovid, a Protease Inhibitor Drug Combination for the Treatment of COVID-19"],"prefix":"10.3390","volume":"16","author":[{"given":"Mikl\u00f3s","family":"Bege","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, University of Debrecen, Egyetem t\u00e9r 1, 4032 Debrecen, Hungary"},{"name":"HUN-REN-DE Molecular Recognition and Interaction Research Group, University of Debrecen, Egyetem t\u00e9r 1, 4032 Debrecen, Hungary"},{"name":"Institute of Healthcare Industry, University of Debrecen, Nagyerdei krt 98, 4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8462-4547","authenticated-orcid":false,"given":"Anik\u00f3","family":"Borb\u00e1s","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, University of Debrecen, Egyetem t\u00e9r 1, 4032 Debrecen, Hungary"},{"name":"HUN-REN-DE Molecular Recognition and Interaction Research Group, University of Debrecen, Egyetem t\u00e9r 1, 4032 Debrecen, Hungary"},{"name":"National Laboratory of Virology, University of P\u00e9cs, Ifj\u00fas\u00e1g \u00fatja 20, 7624 P\u00e9cs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,2]]},"reference":[{"key":"ref_1","unstructured":"Gupta, S.P. 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