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

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.

• Authors: David A Ostrov, Andrew P Bluhm, Danmeng Li, Juveriya Qamar Khan, Megha Rohamare, Karthic Rajamanickam, Kalpana K Bhanumathy, Jocelyne Lew, Darryl Falzarano, Franco J Vizeacoumar, Joyce A Wilson, Marco Mottinelli, Siva Rama Raju Kanumuri, Abhisheak Sharma, Christopher R McCurdy, Michael H Norris
• Journal: Pathogens (Basel, Switzerland) (Pathogens) Vol. 10 Issue 11 (Nov 20 2021) ISSN: 2076-0817 [Print] Switzerland
• PMID: 34832669 (Publication Type: Journal Article)