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Fixing the Achilles Heel of Pfizer’s Paxlovid for COVID-19 Treatment
Lennart Brewitz* and Christopher J. Schofield*
Cite This: https://doi.org/10.1021/acs.jmedchem.4c01342
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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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