key: cord-0754141-8boxq366
authors: Sharma, Ridhima; Magoon, Rohan; Kaushal, Brajesh
title: Closing the portal to SARS-CoV-2 cellular entry: May open newer avenues…
date: 2020-12-22
journal: Med Hypotheses
DOI: 10.1016/j.mehy.2020.110464
sha: e6781c3e3e059ea97af7b70186b9603f2ae32d4b
doc_id: 754141
cord_uid: 8boxq366

nan

Amidst the wide range of challenges posed by COVID-19 associated thrombosis, the Kumar et al proposition of severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) cellular entry based angiotensin converting enzyme 2 (ACE2) signalling alterations being at the cornerstone of endothelial dysfunction and vascular pro-thrombotic environment, can have potentially important therapeutic implications [1, 2] . Taking account of their molecular level description, we wish to highlight a few points to substantiate the clinical perspective of the discussion.

(i) Akin to Kumar and colleagues, the essential role of transmembrane protease serine 2 (TMPRSS2) co-expression in mediating the SARS-CoV-2 cellular entry, has captivated the attention of the fraternity [3] [4] [5] [6] . (ii) In this context, the TMPRSS2 inhibitors such as camostat mesylate (CM) and nafamostat mesylate (NM) are being currently envisaged as promising repurposed drugs (approved for treating pancreatitis in Japan) in COVID-19 for their anti-inflammatory and antiviral properties owing to serine protease inhibition and resultant viral cellular entry block [3] [4] [5] [6] . A few researchers cite an incremental value to the therapeutic inclusion of a critical host factor blocker like TMPRSS2 inhibitor over an isolated antiviral regimen, in conferring a subsequent resilience to the rapidly developing viral resistance. They opine that the isolated viral point mutations are unlikely to accommodate for such a critical host component block [7] . (iii) A recent retrospective observational case-series by Hofmann-Winkler et al outlined an attenuation of the COVID-19 disease severity marked by lower sepsis-related organ failure assessment (SOFA) scores paralleled by an ameliorated inflammatory profile in the six ICU patients who received CM compared to the five ICU patients treated with hydroxychloroquine [3] . The maximum CM dose administered in their evaluation amounted to 2 × 100 mg pills three times daily for 5 days which was in accordance with the protocol of a large Denmark randomized controlled trial (RCT, CamoCo-19, NCT04321096). In addition to the aforementioned, a number of double to quadruple blinded RCTs are also ongoing with the aim of evaluating the role of CM as a monotherapy or as an add-on therapy in COVID-19 patients [4] . (iv) Centralizing the focus on thrombosis as in Kumar et al discussion [1] , NM has additional anticoagulant and antifibrinolytic effects with Asakura and Ogawa suggesting a heparin and NM combination therapy in COVID-19 patients [5, 6] . Interestingly, three elderly high-risk SARS-CoV-2 pneumonia patients with a progressive disease despite antiviral therapy demonstrated an improved clinical profile following administration of 200 mg NM over a span of 24 h [6] .

To conclude, the therapeutic armamentarium against COVID-19 is doubtlessly going to become more SARS-CoV-2 specific as an augmented comprehension of the disease related mechanisms transpires. This is heralded by the exemplar of a comprehensive SARS-CoV-2 cellular level patho-physiological description staged by Kumar et al [1] , in opening distinctly novel and selective therapeutic avenues aimed at the highest priority societal goal of mitigating the COVID-19 associated morbidity and mortality. 

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. 

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