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Pathogens
Volume 10
Issue 11
10.3390/pathogens10111514
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Article

Highly Specific Sigma Receptor Ligands Exhibit Anti-Viral Properties in SARS-CoV-2 Infected Cells

by
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
Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL 32610, USA
2
Department of Geography, University of Florida College of Liberal Arts and Sciences, Gainesville, FL 32611, USA
3
Emerging Pathogens Institute, University of Florida, Gainesville, FL 32610, USA
4
Department of Biochemistry, Microbiology, and Immunology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
5
Division of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
6
Vaccine and Infectious Disease Organization-International Vaccine Centre, University of Saskatchewan, Saskatoon, SK S7N 5E3, Canada
7
Cancer Research Department, Saskatchewan Cancer Agency, Saskatoon, SK S7N 5E5, Canada
8
Department of Medicinal Chemistry, University of Florida College of Pharmacy, Gainesville, FL 32610, USA
9
Department of Pharmaceutics, University of Florida College of Pharmacy, Gainesville, FL 32610, USA
10
Translational Drug Development Core, University of Florida Clinical and Translational Sciences Institute, Gainesville, FL 32610, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Lawrence S. Young
Pathogens 2021, 10(11), 1514; https://doi.org/10.3390/pathogens10111514
Received: 14 October 2021 / Revised: 10 November 2021 / Accepted: 17 November 2021 / Published: 20 November 2021
(This article belongs to the Collection Feature Papers in Viral Pathogens)
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Abstract

(1) Background: There is a strong need for prevention and treatment strategies for COVID-19 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 activity associated with agonism of the sigma-1 receptor (e.g., SA4503), ligation of the sigma-2 receptor (e.g., CM398), and a combination of the two pathways (e.g., AZ66). (3) Results: Intermolecular contacts between these ligands and sigma receptors were identified by structural modeling. (4) Conclusions: Sigma receptor ligands and drugs with off-target sigma receptor binding characteristics were effective at inhibiting SARS-CoV-2 infection in primate and human cells, representing a potential therapeutic avenue for COVID-19 prevention and treatment. View Full-Text
Keywords: drug discovery; sigma-1 receptor; SARS-CoV-2; molecular docking; antiviral therapeutics drug discovery; sigma-1 receptor; SARS-CoV-2; molecular docking; antiviral therapeutics
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MDPI and ACS Style

Ostrov, D.A.; Bluhm, A.P.; Li, D.; Khan, J.Q.; Rohamare, M.; Rajamanickam, K.; K. Bhanumathy, K.; Lew, J.; Falzarano, D.; Vizeacoumar, F.J.; Wilson, J.A.; Mottinelli, M.; Kanumuri, S.R.R.; Sharma, A.; McCurdy, C.R.; Norris, M.H. 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

AMA Style

Ostrov DA, Bluhm AP, Li D, Khan JQ, Rohamare M, Rajamanickam K, K. Bhanumathy K, Lew J, Falzarano D, Vizeacoumar FJ, Wilson JA, Mottinelli M, Kanumuri SRR, Sharma A, McCurdy CR, Norris MH. Highly Specific Sigma Receptor Ligands Exhibit Anti-Viral Properties in SARS-CoV-2 Infected Cells. Pathogens. 2021; 10(11):1514. https://doi.org/10.3390/pathogens10111514

Chicago/Turabian Style

Ostrov, David A., Andrew P. Bluhm, Danmeng Li, Juveriya Q. Khan, Megha Rohamare, Karthic Rajamanickam, Kalpana K. Bhanumathy, Jocelyne Lew, Darryl Falzarano, Franco J. Vizeacoumar, Joyce A. Wilson, Marco Mottinelli, Siva R.R. Kanumuri, Abhisheak Sharma, Christopher R. McCurdy, and Michael H. Norris. 2021. "Highly Specific Sigma Receptor Ligands Exhibit Anti-Viral Properties in SARS-CoV-2 Infected Cells" Pathogens 10, no. 11: 1514. https://doi.org/10.3390/pathogens10111514

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Author Biographies

David Ostrov is an immunologist and structural biologist with experience in structure-based drug design. He received his PhD from the University of Washington; completed postdoctoral training at the Albert Einstein College of Medicine; and is currently a faculty member in the Department of Pathology, Immunology and Laboratory Medicine at the University of Florida College of Medicine.
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