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Fixing the Achilles Heel of Pfizer’s Paxlovid for COVID-19 Treatment

Brewitz et al., Journal of Medicinal Chemistry, doi:10.1021/acs.jmedchem.4c01342
Jul 2024  
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Perspective article discussing the development of ibuzatrelvir (PF-07817883) as a SARS-CoV-2 main protease (Mpro) inhibitor which addresses the metabolic instability of nirmatrelvir and does not require co-administration with ritonavir, thereby avoiding the drawbacks and drug interactions associated with ritonavir in paxlovid.
See Bischof et al. for another review covering paxlovid for COVID-19.
Brewitz et al., 5 Jul 2024, peer-reviewed, 2 authors. Contact:,
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Abstract: This article is licensed under CC-BY 4.0 Viewpoint Fixing the Achilles Heel of Pfizer’s Paxlovid for COVID-19 Treatment Lennart Brewitz* and Christopher J. Schofield* Cite This: See for options on how to legitimately share published articles. ACCESS Read Online Metrics & More Article Recommendations ABSTRACT: Nirmatrelvir (PF-07321332), a first-in-class inhibitor of the severe acute respiratory syndrome coronavirus-2 (SARSCoV-2) main protease (Mpro), was developed by Pfizer under intense pressure during the pandemic to treat COVID-19. A weakness of nirmatrelvir is its limited metabolic stability, which led to the development of a combination therapy (paxlovid), involving coadministration of nirmatrelvir with the cytochrome P450 inhibitor ritonavir. However, limitations in tolerability of the ritonavir component reduce the scope of paxlovid. In response to these limitations, researchers at Pfizer have now developed the secondgeneration Mpro inhibitor PF-07817883 (ibuzatrelvir). Structurally related to nirmatrelvir, including with the presence of a trifluoromethyl group, albeit located differently, ibuzatrelvir manifests enhanced oral bioavailability, so it does not require coadministration with ritonavir. The development of ibuzatrelvir is an important milestone, because it is expected to enhance the treatment of COVID-19 without the drawbacks associated with ritonavir. Given the success of paxlovid in treating COVID-19, it is likely that ibuzatrelvir will be granted approval as an improved drug for treatment of COVID-19 infections, so complementing vaccination efforts and improving pandemic preparedness. The development of nirmatrelvir and ibuzatrelvir dramatically highlights the power of appropriately resourced modern medicinal chemistry to very rapidly enable the development of breakthrough medicines. Consideration of how analogous approaches can be used to develop similarly breakthrough medicines for infectious diseases such as tuberculosis and malaria is worthwhile. N irmatrelvir (PF-07321332; 1) is a first-in-class smallmolecule inhibitor of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) main protease (Mpro/ 3C-like protease), which is used clinically in combination with ritonavir under the brand-name paxlovid to treat and/or hinder SARS-CoV-2 infections (Figure 1a).1,2 Mpro is a nucleophilic cysteine protease that catalyzes the hydrolysis of viral polyproteins pp1a/1ab to give functional nonstructural proteins;3−5 Mpro inhibition disrupts the viral life cycle and halts viral replication.6−8 Work leading to the development of paxlovid, which was carried out under intense time and social pressure during the COVID-19 pandemic, was a major breakthrough, because it validated inhibition of Mpro as a treatment for COVID-19.1,2 Paxlovid treatment complements vaccination campaigns and provides a safe means to cure infections in vulnerable groups;2,9 along with several other clinically approved Mpro inhibitors subsequently reported by others,10−14 it has contributed to reducing the death rate associated with SARS-CoV-2 infections and helped enable a return to pre-COVID-19 lifestyles. Recently, researchers from Pfizer have reported on the development of PF-07817883 (ibuzatrelvir; 2) as a nirmatrelvirderived second-generation orally active Mpro..
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