PAD Inhibitors as a Potential Treatment for SARS-CoV-2 Immunothrombosis

Maheedhara R Guda,Andrew J Tsung,Kiran K Velpula,Narasaraju Teluguakula,Willie Elliott,Swapna Asuthkar,Durbaka V R Prasad

doi:10.3390/biomedicines9121867

Abstract

Since the discovery of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019, the virus’s dynamicity has resulted in the evolution of various variants, including the delta variant and the more novel mu variant. With a multitude of mutant strains posing as challenges to vaccine efficacy, it is critical that researchers embrace the development of pharmacotherapeutics specific to SARS-CoV-2 pathophysiology. Neutrophil extracellular traps and their constituents, including citrullinated histones, display a linear connection with thrombotic manifestations in COVID-19 patients. Peptidylarginine deiminases (PADs) are a group of enzymes involved in the modification of histone arginine residues by citrullination, allowing for the formation of NETs. PAD inhibitors, specifically PAD-4 inhibitors, offer extensive pharmacotherapeutic potential across a broad range of inflammatory diseases such as COVID-19, through mediating NETs formation. Although numerous PAD-4 inhibitors exist, current literature has not explored the depth of utilizing these inhibitors clinically to treat thrombotic complications in COVID-19 patients. This review article offers the clinical significance of PAD-4 inhibitors in reducing thrombotic complications across various inflammatory disorders like COVID-19 and suggests that these inhibitors may be valuable in treating the origin of SARS-CoV-2 immunothrombosis.

Highlights

According to Johns Hopkins Coronavirus Research Center, which tracks the rate of COVID-19 cases over 28 days, as of 14 August 2021, the United States, India, Indonesia, Brazil, and the United Kingdom have been leading in COVID-19 cases with reports well above one million over the last 28 days
In human neutrophils separated from patient sera and added to MM cell lines to induce neutrophil extracellular traps (NETs) formation, BMS-P5 provided more significant reduction of NETosis when compared to GSK-484, a reversible selective PAD4 inhibitor
Such results were consistent when examining mice infected with MM cell-lines that were subsequently provided with a PAD4 inhibitor, reducing symptoms consistent with multiple myeloma, as well as cell free-DNA and citrullinated histones, products associated with NET constituents and NET formation, respectively

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Immunothrombosis, immune-related thrombotic complications, remains a pressing predicament for COVID-19 patients with mild and severe symptoms, often resulting in in-patient use of thromboprophylaxis to prevent the risk of venous thromboembolism [4]. Such prophylactic intervention often involves targeting anti-coagulation factors to assist in coagulation factor breakdown or coagulation factor inhibitors, thereby leading to an approach of treating a product of the cause rather than the origin, especially inflammatory components such as neutrophil extracellular traps (NETs) and NET components, such as citrullinated histones as being the constituents involved in vascular occlusion [5]. Use of peptidylarginine deiminase (PAD) inhibitors, the PAD-4 isozyme, offers valuable insight into controlling products of inflammation that drive immunothrombosis in SARS-CoV-2

Netosis and Citrullinated Histones Potentiate Immunothrombosis

Overview of PADs and Significance in SARS-CoV-2

Current Treatment of SARS-CoV-2 Immunothrombosis

PAD-4 Inhibitors as Therapeutic Agents and Potential as a COVID-19 Treatment

Conclusions