Abstract: pathogens Article Highly Specific Sigma Receptor Ligands Exhibit Anti-Viral Properties in SARS-CoV-2 Infected Cells David A. Ostrov 1 , Andrew P. Bluhm 2,3 , Danmeng Li 1 , Juveriya Qamar Khan 4 , Megha Rohamare 4 , Karthic Rajamanickam 5 , Kalpana K. Bhanumathy 5 , Jocelyne Lew 6 , Darryl Falzarano 6 , Franco J. Vizeacoumar 5,7 , Joyce A. Wilson 4 , Marco Mottinelli 8 , Siva Rama Raju Kanumuri 9,10 , Abhisheak Sharma 9,10 , Christopher R. McCurdy 8,10 and Michael H. Norris 2,3, * 1 2 3 4 5 6



 7 8 Citation: Ostrov, D.A.; Bluhm, A.P.; Li, D.; Khan, J.Q.; Rohamare, M.; Rajamanickam, K.; K. Bhanumathy, 9 10 K.; Lew, J.; Falzarano, D.; Vizeacoumar, F.J.; et al. Highly Specific Sigma Receptor Ligands Exhibit Anti-Viral Properties in SARS-CoV-2 Infected Cells. Pathogens 2021, 10, 1514. https://doi.org/ 10.3390/pathogens10111514 Academic Editor: Lawrence S. Young Received: 14 October 2021 Accepted: 17 November 2021 Published: 20 November 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/). * Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL 32610, USA; ostroda@pathology.ufl.edu (D.A.O.); dameng1986@ufl.edu (D.L.) Department of Geography, University of Florida College of Liberal Arts and Sciences, Gainesville, FL 32611, USA; abluhm@ufl.edu Emerging Pathogens Institute, University of Florida, Gainesville, FL 32610, USA Department of Biochemistry, Microbiology, and Immunology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada; jqk913@mail.usask.ca (J.Q.K.); mrr968@mail.usask.ca (M.R.); joyce.wilson@usask.ca (J.A.W.) Division of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada; kar029@mail.usask.ca (K.R.); kak677@mail.usask.ca (K.K.B.); franco.vizeacoumar@usask.ca (F.J.V.) Vaccine and Infectious Disease Organization-International Vaccine Centre, University of Saskatchewan, Saskatoon, SK S7N 5E3, Canada; jocelyne.lew@usask.ca (J.L.); darryl.falzarano@usask.ca (D.F.) Cancer Research Department, Saskatchewan Cancer Agency, Saskatoon, SK S7N 5E5, Canada Department of Medicinal Chemistry, University of Florida College of Pharmacy, Gainesville, FL 32610, USA; m.mottinelli@cop.ufl.edu (M.M.); cmccurdy@cop.ufl.edu (C.R.M.) Department of Pharmaceutics, University of Florida College of Pharmacy, Gainesville, FL 32610, USA; kanumuris@cop.ufl.edu (S.R.R.K.); asharma1@cop.ufl.edu (A.S.) Translational Drug Development Core, University of Florida Clinical and Translational Sciences Institute, Gainesville, FL 32610, USA Correspondence: mhnorris@ufl.edu Abstract: (1) Background: There is a strong need for prevention and treatment strategies for COVID19 that are not impacted by SARS-CoV-2 mutations emerging in variants of concern. After virus infection, host ER resident sigma receptors form direct interactions with non-structural SARS-CoV-2 proteins present in the replication complex. (2) Methods: In this work, highly specific sigma receptor ligands were investigated for their ability to inhibit both SARS-CoV-2 genome replication and virus induced cellular toxicity. This study found antiviral..