Abstract: Article Paracetamol Is Associated with a Lower Risk of COVID-19 Infection and Decreased ACE2 Protein Expression: A Retrospective Analysis Nuno Santos Leal † , Yizhou Yu † , Yuwen Chen , Giorgio Fedele and Luís Miguel Martins * MRC Toxicology Unit, Gleeson Building, Tennis Court Road, University of Cambridge, Cambridge CB2 1QR, UK; njs76@mrc-tox.cam.ac.uk (N.S.L.); yzy21@cam.ac.uk (Y.Y.); yc487@cam.ac.uk (Y.C.); gf334@mrc-tox.cam.ac.uk (G.F.) * Correspondence: martins.lmiguel@gmail.com † These authors contributed equally to this work.



 Citation: Leal, N.S.; Yu, Y.; Chen, Y.; Fedele, G.; Martins, L.M. Paracetamol Is Associated with a Lower Risk of COVID-19 Infection and Decreased ACE2 Protein Expression: A Abstract: Ibuprofen is a common over-the-counter drug taken for pain relief. However, recent studies have raised concerns about its potential toxic effect with coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has been proposed that ibuprofen may increase levels of angiotensin-converting enzyme 2 (ACE2), the human receptor for SARS-CoV-2 infection. Therefore, paracetamol is suggested as an alternative to ibuprofen for treating COVID-19 symptoms. Nevertheless, the relationship between intake of paracetamol or ibuprofen and either susceptibility to infection by SARS-CoV-2 or modulation of cellular ACE2 levels remains unclear. In this study, we combined data from human medical records and cells in culture to explore the role of the intake of these drugs in COVID-19. Although ibuprofen did not influence COVID-19 infectivity or ACE2 levels, paracetamol intake was associated with a lower occurrence of COVID-19 in our cohort. We also found that paracetamol led to decreased ACE2 protein levels in cultured cells. Our work identifies a putative protective effect of paracetamol against SARS-CoV2 infection. Future work should explore the molecular mechanisms underlying the relationship between paracetamol and COVID-19. Retrospective Analysis. COVID 2021, 1, 218–229. https://doi.org/10.3390/ Keywords: paracetamol; acetaminophen; ibuprofen; ACE2; COVID-19; SARS-CoV-2; UK Biobank covid1010018 Academic Editor: Konstantinos Poulas Received: 7 July 2021 Accepted: 10 August 2021 Published: 16 August 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).