Available online 2 November 2022

Nirmatrelvir and its metabolites inhibit SARS-CoV-2 replication by binding and suppressing its protease Mpro.

Ritonavir increases the antiviral efficacy of nirmatrelvir by slowing metabolism and occupying PPB sites.

Nirmatrelvir may cause a second round of COVID-19 symptoms, embryonic developmental toxicity and changes in host gene expression.

The chiral structure plays a key role in the antiviral activity of nirmatrelvir.

The antiviral activity of compounds 12-18 is similar to or higher than that of nirmatrelvir.

On 22 December 2021, the United States Food and Drug Administration (FDA) approved the first Mpro inhibitor, i.e., oral antiviral nirmatrelvir (PF-07321332)/ritonavir (Paxlovid), for the treatment of early severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Nirmatrelvir inhibits SARS-CoV-2 infection, but high doses or long-term treatment may cause embryonic developmental toxicity and changes in host gene expression. The chiral structure of nirmatrelvir plays a key role in its antiviral activity. Ritonavir boosts the efficacy of nirmatrelvir by inactivating cytochrome P450 3A4 (CYP3A4) expression and occupying the plasma protein binding sites. Multidrug resistance protein 1 (MDR1) inhibitors may increase the efficacy of nirmatrelvir. However, paxlovid has many contraindications. Some patients treated with paxlovid experience a second round of coronavirus disease 2019 (COVID-19) symptoms soon after recovery. Interestingly, the antiviral activity of nirmatrelvir metabolites, such as compounds 12−18, is similar to or higher than that of nirmatrelvir. Herein, we review the advances and challenges in using nirmatrelvir and its derivatives with the aim of providing knowledge to drug developers and physicians in the fight against COVID-19.

Nirmatrelvir

Pharmacology

Pharmacokinetics

Toxicology

Derivatives

COVID-19

© 2022 The Author(s). Published by Elsevier B.V. on behalf of Xi’an Jiaotong University.