Abstract: viruses Article The Combination of Bromelain and Acetylcysteine (BromAc) Synergistically Inactivates SARS-CoV-2 Javed Akhter 1,2,† , Grégory Quéromès 3,† , Krishna Pillai 2,† , Vahan Kepenekian 1,4,† , Samina Badar 1,5 , Ahmed H. Mekkawy 1,2,5 , Emilie Frobert 3,6,‡ , Sarah J. Valle 1,2,5,‡ and David L. Morris 1,2,5, *,‡ 1 2 3 4 5 6 * † ‡



 Department of Surgery, St. George Hospital, Sydney, NSW 2217, Australia; Javed.Akhter@health.nsw.gov.au (J.A.); vahan.kepenekian@chu-lyon.fr (V.K.); samina.badar@unsw.edu.au (S.B.); z3170073@ad.unsw.edu.au (A.H.M.); sarah.valle@mucpharm.com (S.J.V.) Mucpharm Pty Ltd., Sydney, NSW 2217, Australia; panthera6444@yahoo.com.au CIRI, Centre International de Recherche en Infectiologie, Team VirPatH, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007 Lyon, France; gregory.queromes@univ-lyon1.fr (G.Q.); emilie.frobert@chu-lyon.fr (E.F.) Hospices Civils de Lyon, EMR 3738 (CICLY), Lyon 1 Université, F-69921 Lyon, France St. George & Sutherland Clinical School, University of New South Wales, Sydney, NSW 2217, Australia Laboratoire de Virologie, Institut des Agents Infectieux (IAI), Hospices Civils de Lyon, Groupement Hospitalier Nord, F-69004 Lyon, France Correspondence: david.morris@unsw.edu.au; Tel.: +61-(02)-91132590 These authors contributed equally to this work. These authors contributed equally to this work. A. Aljabali Abstract: Severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection is the cause of a worldwide pandemic, currently with limited therapeutic options. The spike glycoprotein and envelope protein of SARS-CoV-2, containing disulfide bridges for stabilization, represent an attractive target as they are essential for binding to the ACE2 receptor in host cells present in the nasal mucosa. Bromelain and Acetylcysteine (BromAc) has synergistic action against glycoproteins by breakage of glycosidic linkages and disulfide bonds. We sought to determine the effect of BromAc on the spike and envelope proteins and its potential to reduce infectivity in host cells. Recombinant spike and envelope SARS-CoV-2 proteins were disrupted by BromAc. Spike and envelope protein disulfide bonds were reduced by Acetylcysteine. In in vitro whole virus culture of both wild-type and spike mutants, SARS-CoV-2 demonstrated a concentration-dependent inactivation from BromAc treatment but not from single agents. Clinical testing through nasal administration in patients with early SARS-CoV-2 infection is imminent. Received: 31 January 2021 Keywords: SARS-CoV-2; Bromelain; Acetylcysteine; BromAc; drug repurposing Citation: Akhter, J.; Quéromès, G.; Pillai, K.; Kepenekian, V.; Badar, S.; Mekkawy, A.H.; Frobert, E.; Valle, S.J.; Morris, D.L. The Combination of Bromelain and Acetylcysteine (BromAc) Synergistically Inactivates SARS-CoV-2. Viruses 2021, 13, 425. https://doi.org/10.3390/v13030425 Academic Editors: Kenneth Lundstrom and Alaa A. Accepted: 1 March 2021 Published: 6 March 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/).