Possible Role of Adenosine in COVID-19 Pathogenesis and Therapeutic Opportunities.

Jonathan D Geiger,Madhuvika Murugan,Nabab Khan,Detlev Boison

doi:10.3389/fphar.2020.594487

Abstract

The outbreak of the novel coronavirus disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2) requires urgent clinical interventions. Crucial clinical needs are: 1) prevention of infection and spread of the virus within lung epithelia and between people, 2) attenuation of excessive lung injury in Advanced Respiratory Distress Syndrome, which develops during the end stage of the disease, and 3) prevention of thrombosis associated with SARS-CoV-2 infection. Adenosine and the key adenosine regulators adenosine deaminase (ADA), adenosine kinase (ADK), and equilibrative nucleoside transporter 1 may play a role in COVID-19 pathogenesis. Here, we highlight 1) the non-enzymatic role of ADA by which it might out-compete the virus (SARS-CoV-2) for binding to the CD26 receptor, 2) the enzymatic roles of ADK and ADA to increase adenosine levels and ameliorate Advanced Respiratory Distress Syndrome, and 3) inhibition of adenosine transporters to reduce platelet activation, thrombosis and improve COVID-19 outcomes. Depending on the stage of exposure to and infection by SARS-CoV-2, enhancing adenosine levels by targeting key adenosine regulators such as ADA, ADK and equilibrative nucleoside transporter 1 might find therapeutic use against COVID-19 and warrants further investigation.

Highlights

Coronavirus disease 2019 (COVID-19) is a global pandemic caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) (Guo et al, 2020)
Inhibition of adenosine transport by targeting equilibrative nucleoside transporters type 1 (ENT1) using dipyridamole can enhance adenosine levels and may ameliorate inflammatory processes associated with coronavirus infection
dipeptidyl peptidase 4 (DPP4) inhibitors are widely used clinically and have been shown to enhance clinical outcomes and reduce mortality in diabetes mellitus patients with COVID-19 (Mirani et al, 2020; Rhee et al, 2020; Solerte et al, 2020). This improvement may not be due to antiviral actions of these drugs but rather immune modulation and/or decreased inflammatory responses because such inhibitors were unable to block MERSCoV infection (Strollo and Pozzilli, 2020). These reports provide preliminary evidence that treatment with Sitagliptin, a DPP-4 inhibitor, reduced mortality in patients with type 2 diabetes hospitalized for COVID-19

Summary

Introduction

Coronavirus disease 2019 (COVID-19) is a global pandemic caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) (Guo et al, 2020). Therapeutic strategies are needed immediately to decrease viral spread, significantly attenuate acute respiratory distress, and reduce mortality and morbidities associated with COVID-19. Inhibition of adenosine transport by targeting equilibrative nucleoside transporters type 1 (ENT1) using dipyridamole can enhance adenosine levels and may ameliorate inflammatory processes associated with coronavirus infection.

Results

Conclusion