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Review
. 2022 Jun;35(3):236-240.
doi: 10.37201/req/002.2022. Epub 2022 Feb 21.

[Nirmatrelvir plus ritonavir (Paxlovid) a potent SARS-CoV-2 3CLpro protease inhibitor combination]

[Article in Spanish]
J Reina  1 , C Iglesias
Affiliations
Review

[Nirmatrelvir plus ritonavir (Paxlovid) a potent SARS-CoV-2 3CLpro protease inhibitor combination]

[Article in Spanish]
J Reina et al. Rev Esp Quimioter. 2022 Jun.

Abstract
in English, Spanish

All coronavirus, including SARS-CoV-2, encode two proteases needed for the processing of PP1A and PP1AB polyproteins. The main protease 3CL (chemotripsine-like) gives rise to the formation of NSP11/16 proteins. The 3CL protease has been constituted as one of the possible therapeutic targets for the development of antiviral drugs against SARS-COV-2 due to its highly conserved sequence and structure among all coronaviruses. During the SARS-COV-1 pandemic, a hydroxymethyl ketone derivative (PF-00835231) was identified with an intense inhibitory activity against the 3CL protease. Subsequent chemical modifications gave rise to derivative PF-07321332 (nirmatrelvir) which has shown a high antiviral efficacy against SARS-COV-2. The company's data indicate that it is capable of reducing 89% the risk of hospitalization and death of patients infected with hardly adverse effects. Its effectiveness improves if it is administered orally in the first 24-48 hours and the duration of treatment has been established between 3-5 days. The commercial form has been associated with the antiviral ritonavir that has shown the metabolism of nirmatrelvir, lengthening its average life. This antiviral would be effective against current and future viral variants, since 3CL is not modified in them. The FDA approved this antiviral in November 2021 and EMA is in the final evaluation phase.

Todos los coronavirus, incluido el SARS-CoV-2, codifican dos proteasas necesarias para el procesado de las poliproteínas pp1a y pp1ab. La proteasa principal 3CL (quimiotripsina-like) da lugar a la formación de las proteínas nsp11/16. La proteasa 3CL se ha constituido como una de las posibles dianas terapéuticas para el desarrollo de fármacos antivirales frente al SARS-CoV-2 debido a su secuencia y estructura altamente conservada entre todos los coronavirus. Durante la pandemia del SARS-CoV-1 se identificó un derivado hidroximetilcetona (PF-00835231) con una intensa actividad inhibidora frente a la proteasa 3CL. Las modificaciones químicas posteriores dieron lugar al derivado PF-07321332 (nirmatrelvir) que ha mostrado una elevada eficacia antiviral frente al SARS-CoV-2. Los datos de la compañía indican que es capaz de reducir un 89% el riesgo de hospitalización y fallecimiento de los pacientes infectados con apenas efectos adversos. Su eficacia mejora si se administra por vía oral en las primeras 24-48 horas y la duración del tratamiento se ha establecido entre 3-5 días. La forma comercial lleva asociada el antiviral ritonavir que ha mostrado enlentecer el metabolismo de nirmatrelvir, alargando su vida media. Este antiviral sería eficaz frente a las actuales y futuras variantes virales, ya que la 3CL no se modifica en ellas. La FDA aprobó este antiviral en noviembre de 2021 y la EMA está en fase de evaluación final.

Keywords: Nirmatrelvir; PF-07321332; Paxlovid; SARS-CoV-2; antiviral.

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Conflict of interest statement

Los autores declaran no tener ningún conflicto de intereses

Figures

Figura 1
Figura 1
Estructura esquemática del genoma del SARS-CoV-2, proteasas y puntos de corte de las mismas (modificado de Zhu et al.[14]).
Figura 2
Figura 2
Activación por parte de las fosfatasas alcalinas celulares del pro-fármaco PF-07304814 a su forma activa PF-07321332 (nirmatrelvir).
See this image and copyright information in PMC

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