Upregulation of the Renin-Angiotensin System Pathways and SARS-CoV-2 Infection: The Rationale for the Administration of Zinc-Chelating Agents in COVID-19 Patients.

Loris Zamai

doi:10.3390/cells10030506

Abstract

The article describes the rationale for the administration of zinc-chelating agents in COVID-19 patients. In a previous work I have highlighted that the binding of the SARS-CoV spike proteins to the zinc-metalloprotease ACE2 has been shown to induce ACE2 shedding by activating the zinc-metalloprotease ADAM17, which ultimately leads to systemic upregulation of ACE2 activity. Moreover, based on experimental models, it was also shown the detrimental effect of the excessive systemic activity of ACE2 through its downstream pathways, which leads to “clinical” manifestations resembling COVID-19. In this regard, strong upregulation of circulating ACE2 activity was recently reported in COVID-19 patients, thus supporting the previous hypothesis that COVID-19 may derive from upregulation of ACE2 activity. Based on this, a reasonable hypothesis of using inhibitors that curb the upregulation of both ACE2 and ADAM17 zinc-metalloprotease activities and consequent positive feedback-loops (initially triggered by SARS-CoV-2 and subsequently sustained independently on viral trigger) is proposed as therapy for COVID-19. In particular, zinc-chelating agents such as citrate and ethylenediaminetetraacetic acid (EDTA) alone or in combination are expected to act in protecting from COVID-19 at different levels thanks to their both anticoagulant properties and inhibitory activity on zinc-metalloproteases. Several arguments are presented in support of this hypothesis and based on the current knowledge of both beneficial/harmful effects and cost/effectiveness, the use of chelating agents in the prevention and therapy of COVID-19 is proposed. In this regard, clinical trials (currently absent) employing citrate/EDTA in COVID-19 are urgently needed in order to shed more light on the efficacy of zinc chelators against SARS-CoV-2 infection in vivo.

Highlights

The novel severe acute respiratory syndrome (SARS)-CoV-2 pandemic has led to a worldwide health and socioeconomic crisis
It is not clear how COVID-19 comorbid patients having a high constitutive amount of circulating ACE2 may benefit from recombinant ACE2 (rACE2) administration, suggesting that the assumption that the ACE2 activity is down-regulated by SARS-CoV-2 may not be correct
Oral administration of ranitidine bismuth citrate in humans has a well-documented safety profile; bismuth is poorly absorbed in the gastrointestinal tract, and the successful clinical outcome in vivo uses systemic administration [10]

Summary

Introduction

The novel SARS-CoV-2 pandemic has led to a worldwide health and socioeconomic crisis. Whether global herd immunity by vaccination will be hardly achievable, yearly SARS-CoV-2 vaccinations (as for influenza) of people at risk of severe forms will be instead feasible to urgently protect this (minority) part of the population. In this regard, other authors and I have already highlighted that individuals with low probability to survive to SARS-CoV-2 infection are usually elderly with comorbidities correlating with pre-existing high levels of circulating ACE2 concentration/activity that could be used as a prognostic marker [3,7,8,9]. In light of these considerations, it is important to continue to search for new pharmacological treatments for COVID-19

Anti-SARS-CoV-2 Bismuth-Based Drugs

Crucial Role of IL-10 in COVID-19 Pathogenesis

Targeting of SARS-CoV-2-Upregulated Zinc-Dependent Pathways

Findings

Conclusions