nutrients Article L-Carnitine Tartrate Downregulates the ACE2 Receptor and Limits SARS-CoV-2 Infection Aouatef Bellamine 1, *, Tram N. Q. Pham 2 , Jaspreet Jain 2 , Jacob Wilson 3 , Kazim Sahin 4 , Frederic Dallaire 2 , Nabil G. Seidah 2 , Shane Durkee 1 , Katarina Radoševi´ c 5 and Éric A. Cohen 2,6, *   Citation: Bellamine, A.; Pham, T.N.Q.; Jain, J.; Wilson, J.; Sahin, K.; Dallaire, F.; Seidah, N.G.; Durkee, S.; Radoševi´ c, K.; Cohen, É.A. L-Carnitine Tartrate Downregulates the ACE2 Receptor and Limits SARS-CoV-2 Infection. Nutrients 2021, 13, 1297. https://doi.org/10.3390/ nu13041297 Academic Editor: Carlo Agostoni and Gregorio Paolo Milani Received: 15 March 2021 Accepted: 12 April 2021 Published: 14 April 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. 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/). 1 Lonza Consumer Health, Morristown, NJ 07960, USA; shane.durkee@lonza.com 2 Institut de Recherche Clinique de Montreal, Montreal, QC H2W1R7, Canada; Tram.Pham@ircm.qc.ca (T.N.Q.P.); Jaspreet.Jain@ircm.qc.ca (J.J.); frederic.dallaire@ircm.qc.ca (F.D.); Nabil.Seidah@ircm.qc.ca (N.G.S.) 3 Applied Science and Performance Institute, Tampa, FL 33607, USA; jwilson@theaspi.com 4 Department of Animal Nutrition, Faculty of Veterinary Medicine, Firat University, Elazig 23119, Turkey; nsahinkm@yahoo.com 5 Biologics R&D, Lonza Pharma & Biotech, 4057 Basel, Switzerland; katarina.radosevic@lonza.com 6 Departmentof Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, QC H3T 1J4, Canada * Correspondence: aouatef.bellamine@lonza.com (A.B.); eric.Cohen@ircm.qc.ca (É.A.C.) Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been responsible for one of the worst pandemics in modern history. Several prevention and treatment strategies have been designed and evaluated in recent months either through the repurposing of existing treatments or the development of new drugs and vaccines. In this study, we show that L-carnitine tartrate supplementation in humans and rodents led to significant decreases of key host dependency factors, notably angiotensin-converting enzyme 2 (ACE2), transmembrane protease serine 2 (TMPRSS2), and Furin, which are responsible for viral attachment, viral spike S-protein cleavage, and priming for viral fusion and entry. Interestingly, pre-treatment of Calu-3, human lung epithelial cells, with L-carnitine tartrate led to a significant and dose-dependent inhibition of the infection by SARS-CoV-2. Infection inhibition coincided with a significant decrease in ACE2 mRNA expression levels. These data suggest that L-carnitine tartrate should be tested with appropriate trials in humans for the possibility to limit SARS-CoV-2 infection. Keywords: L-carnitine; SARS-CoV-2; COVID-19; exercise; inflammation; ACE-2; Furin; TMPRSS2 1. Introduction Severe acute respiratory syndrome coronavirus (SARS-CoV-1 and SARS-CoV-2) is responsible for the SARS epidemic from 2002 to 2004 and more recently for the coronavirus disease 2019 (COVID-19) pandemic outbreak initially detected in December 2019 in Wuhan China [1]. The rapid spread of the disease has affected more than 120 million people and caused over 2.6 million deaths in 220 countries as per mid-March of 2021 [2]. SARS-CoV-2 is an airborne virus that affects mainly the lungs and the upper respiratory system [2], leading ultimately to lung injury, respiratory distress, and death in severe cases. According to recent data released, there are 237 known vaccine candidates globally, of which 64 are in clinical evaluation and nine are in their phase III clinical stage [3,4]. A few vaccines starting with Pfizer-BioNTech and Moderna’s mRNA-based vaccines and more recently Johnson & Johnson’s single-shot adenovirus vector-based vaccine have been approved for adult use [5]. As a result of the urgency of the situation, accelerated clinical development paths have been followed [3,6] and resulted in decreased vaccine acceptance [6]. In addition to the vaccines, there are a number of other preventive and therapeutic strategies being developed, including antibodies [7,8] and antiviral drugs [9,10]. Nutrients 2021, 13, 1297. https://doi.org/10.3390/nu13041297 https://www.mdpi.com/journal/nutrients