Cysteamine with In Vitro Antiviral Activity and Immunomodulatory Effects Has the Potential to Be a Repurposing Drug Candidate for COVID-19 Therapy.

Tonino Alonzi,Linda Petrone,Federica Rossin,Concetta Castilletti,Manuela D’Eletto,Laura Falasca,Giuseppe Ippolito,Giovanni Delogu,Maria Rosaria Capobianchi,Mauro Piacentini,Delia Goletti,Alessandra Aiello,Roberta Nardacci,Saeid Najafi Fard

doi:10.3390/cells11010052

Abstract

The ongoing pandemic of coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), needs better treatment options both at antiviral and anti-inflammatory levels. It has been demonstrated that the aminothiol cysteamine, an already human applied drug, and its disulfide product of oxidation, cystamine, have anti-infective properties targeting viruses, bacteria, and parasites. To determine whether these compounds exert antiviral effects against SARS-CoV-2, we used different in vitro viral infected cell-based assays. Moreover, since cysteamine has also immune-modulatory activity, we investigated its ability to modulate SARS-CoV-2-specific immune response in vitro in blood samples from COVID-19 patients. We found that cysteamine and cystamine decreased SARS-CoV-2-induced cytopathic effects (CPE) in Vero E6 cells. Interestingly, the antiviral action was independent of the treatment time respect to SARS-CoV-2 infection. Moreover, cysteamine and cystamine significantly decreased viral production in Vero E6 and Calu-3 cells. Finally, cysteamine and cystamine have an anti-inflammatory effect, as they significantly decrease the SARS-CoV-2 specific IFN-γ production in vitro in blood samples from COVID-19 patients. Overall, our findings suggest that cysteamine and cystamine exert direct antiviral actions against SARS-CoV-2 and have in vitro immunomodulatory effects, thus providing a rational to test these compounds as a novel therapy for COVID-19.

Highlights

Coronavirus disease 2019 (COVID-19), which is caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global concern due to its high transmissibility and pathogenicity [1]
We demonstrated that cysteamine and its disulfide product of oxidation cystamine display potent in vitro antiviral activity against SARS-CoV-2 and ex vivo immunomodulatory properties in blood cells from COVID-19 patients
Using different cell lines, we showed that treatment with cysteamine or cystamine exerted antiviral activity by impairing SARS-CoV-2 replication, as clearly highlighted by the presence of very few viral particles in the infected cells upon cysteamine treatment in the electron microscopy images

Summary

Introduction

Coronavirus disease 2019 (COVID-19), which is caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global concern due to its high transmissibility and pathogenicity [1]. Cysteamine and its disulfide product of oxidation, cystamine, exert many biological effects; for example, they can act as exogenous supplements for L-cysteine transport into the cells for the synthesis of glutathione, an important antioxidant agent. These compounds, influence the oxidative state of the cells, regulating several signaling pathways involved in the important mechanisms of cellular homeostasis [9]. Cysteamine has been shown as one of the earliest known pharmacological inhibitors of transglutaminase 2 (TG2) [10], an ubiquitous enzyme involved in several important cellular processes, such as cell death/survival and autophagy [6]

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