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Biologics and Small Molecules in the Treatment of COVID-19

June 2020 | Volume 19 | Issue 6 | Features | 673 | Copyright © June 2020


Published online May 20, 2020

Dedee F. Murrell , Lidia Rudnicka , Swathi Shivakumar , Martin Kassir , Mohammad Jafferany , Hassan Galadari , Torello Lotti , Roxanna Sadoughifar , Zuzanna Sitkowska , Mohamad Goldust

aDepartment of Dermatology, St George Hospital, Faculty of Medicine, University of New South Wales, Sydney, Australia bDepartment of Dermatology, Medical University of Warsaw, Warsaw, Poland cCosmetiq Clinic, Pettah-Chacka Road, Trivandrum, Kerala, India dFounding director, Worldwide laser institute, Dallas, TX eCentral Michigan University, Saginaw, MI fCollege of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates gUniversity of Studies Guglielmo Marconi, Rome, Italy hUniversity of Rome G. Marconi, Rome, Italy; Bidarskincenter Tehran, Iran iDepartment of Dermatology, Medical University of Warsaw, Warsaw, Poland jUniversity of Rome G. Marconi, Rome, Italy; Department of Dermatology, University Hospital Basel, Basel, Switzerland

Abstract

INTRODUCTION

The novel corona virus disease (COVID-19) is caused by a virus belonging to the betacorona virus family.1 The highly infectious nature of the disease, ability to spread through asymptomatic carriers, as well as the lack of a vaccine, have led to its uncontrolled spread worldwide since its inception in Wuhan, China in December 2019. The current reported number of cases is 6,13,882 worldwide with a death toll of 28,231 as of March 28, 2020. Hence, our immediate urgent challenge is to find effective drugs for the management of this disease.1-4

The National Health Commission of China issued pharmaceutical guidelines for the management of COVID-19, which has since undergone 5 rounds of modification. Currently, anti-viral drugs including protease inhibitors and nucleoside reverse transcriptase inhibitors, Interferon (IFN)-alfa, chloroquine, and arbidol are being used for a duration of 10 days. Newer drugs including Favirapir and Remdisavir have shown good results.5

The pathogenesis of COVID-19 involves binding to its receptor, ACE2 (angiotensin converting enzyme-2) protein, and using the cellular protease TMPRSS2 to enter target cells.6 Therefore, a TMPRSS2 inhibitor would block entry of the virus and thus constitute a valuable treatment option. Imatinib, a BCR-ABL kinase inhibitor, inhibits the fusion of virions with the endosomal membrane.7 Patients taking drugs that upregulate ACE2 receptors (including ACE inhibitors and ARB blockers) should have these ceased or other drug classes substituted. As these ACE2 receptors are expressed not only in the alveolar tissue of the lungs but also the eyes, oral mucosa, and intestine, and endothelial cells in blood vessels, contamination of broken skin such as atopic dermatitis, blistering diseases, and psoriasis, if allowed to relapse or be unprotected, could be dangerous.8

Given the routes of transmission of this coronavirus, it is imperative that health care workers are provided with adequate personal protective clothing – N95 masks (which can be re-sterilized using a protocol recently developed at Duke University if in short supply, by research labs),9 goggles without ventilation, and complete gowning; those in lower risk areas of hospitals need patients wearing masks and health care workers at the least in N95 masks and goggles because humans can be asymptomatic for at least 5 days while spreading the virus and because it persists in the air and ventilation system on droplets and surfaces and gloves if sampling broken skin and mucosae.10

Cytokine involvement in the pathogenesis of COVID-19 infection is diverse. In particular, IFN-1 production is dysregulated. cGAS, ALK, and STING cytokines are suggested as potential therapeutic targets to prevent the cytokine storm. Cytokine directed antagonists, such as adalimumab (TNF-α) and CMAB806 (IL-6) are currently under clinical trials against COVID-19.11,12 Sorafenib is a potent inhibitor of the STING pathway, and hence a potential candidate in trials.13 Anaplastic lymphoma kinase (ALK) inhibitors were reported to be effective STING antagonists both in vitro and in vivo. Thus, ALK-targeted drugs have great potential in treating moderate to severe lung inflammation in COVID-19.14 Suramin, an effective cGAS antagonist acts as an entry inhibitor for different type of viruses.15 Clinical trial of Suramin for COVID-19 is already underway.16

In another study, clinical data of COVID-19 positive patients showed a rise in IL-6, which reduced with treatment. Hence, it is hypothesized that antibodies targeting IL-6 or IL-6R may be a novel treatment option, especially in those with severe symptoms.17 The humanized anti-human IL-6 receptor monoclonal antibody, tocilizumab, can specifically bind sIL-6R and mIL-6R