Sigma Receptor Ligands Prevent COVID Mortality In Vivo: Implications for Future Therapeutics
Reed L Berkowitz, Andrew P Bluhm, Glenn W Knox, Christopher R Mccurdy, David A Ostrov, Michael H Norris
International Journal of Molecular Sciences, doi:10.3390/ijms242115718
The emergence of lethal coronaviruses follows a periodic pattern which suggests a recurring cycle of outbreaks. It remains uncertain as to when the next lethal coronavirus will emerge, though its eventual emergence appears to be inevitable. New mutations in evolving SARS-CoV-2 variants have provided resistance to current antiviral drugs, monoclonal antibodies, and vaccines, reducing their therapeutic efficacy. This underscores the urgent need to investigate alternative therapeutic approaches. Sigma receptors have been unexpectedly linked to the SARS-CoV-2 life cycle due to the direct antiviral effect of their ligands. Coronavirus-induced cell stress facilitates the formation of an ER-derived complex conducive to its replication. Sigma receptor ligands are believed to prevent the formation of this complex. Repurposing FDA-approved drugs for COVID-19 offers a timely and cost-efficient strategy to find treatments with established safety profiles. Notably, diphenhydramine, a sigma receptor ligand, is thought to counteract the virus by inhibiting the creation of ER-derived replication vesicles. Furthermore, lactoferrin, a well-characterized immunomodulatory protein, has shown antiviral efficacy against SARS-CoV-2 both in laboratory settings and in living organisms. In the present study, we aimed to explore the impact of sigma receptor ligands on SARS-CoV-2-induced mortality in ACE2-transgenic mice. We assessed the effects of an investigational antiviral drug combination comprising a sigma receptor ligand and an immunomodulatory protein. Mice treated with sigma-2 receptor ligands or diphenhydramine and lactoferrin exhibited improved survival rates and rapid rebound in mass following the SARS-CoV-2 challenge compared to mock-treated animals. Clinical translation of these findings may support the discovery of new treatment and research strategies for SARS-CoV-2.
Institutional Review Board Statement: The studies and SOPs were approved by the University of Florida Institutional Biosafety Committee under protocol BIO5594. They were carried out in the University of Florida Environmental Health and Safety inspected and approved BSL3 and ABSL3 facilities. Ethical approval for the animal studies and procedures in this work were approved by the University of Florida IACUC under protocol #202111322. Humane endpoints and euthanasia guidelines according to the American Veterinary Medical Association were adhered to throughout the study.
Informed Consent
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