Inhibition of SARS-CoV-2 entry through the ACE2/TMPRSS2 pathway: a promising approach for uncovering early COVID-19 drug therapies

Georgia Ragia, Vangelis G Manolopoulos, Georgia Ragia, Vangelis G Manolopoulos

Abstract

Aim: The COVID-19 pandemic caused by infection with the novel coronavirus SARS-CoV-2 is urging the scientific community worldwide to intense efforts for identifying and developing effective drugs and pharmacologic strategies to treat the disease. Many of the drugs that are currently in (pre)clinical development are addressing late symptoms of the disease. This review focuses on potential pharmacologic intervention at an early stage of infection which could result in less-infected individuals and less cases with severe COVID-19 disease due to reduced virus entry into the cells.

Method: We scanned the literature for evidence on drugs that target the virus entry machinery into host cells and consist mainly of ACE2 and TMPRSS2, as well as other cellular molecules regulating ACE2 expression, such as ADAM-17 and calmodulin.

Results: Several drugs/drug classes have been identified. Most of them are already used clinically for other indications. They include recombinant soluble ACE2, indirect ACE2 modulators (angiotensin receptor blockers, calmodulin antagonists, selective oestrogen receptor modifiers), TMPRSS2 inhibitors (camostat mesylate, nafamostat mesylate, antiandrogens, inhaled corticosteroids) and ADAM-17 enhancers (5-fluorouracil).

Conclusion: Several agents have potential for prophylactic and therapeutic intervention at the early stages of SARS-CoV-2 infection and COVID-19 disease and they should be urgently investigated further in appropriate preclinical models and clinical studies.

Keywords: 5-fluorouracil; ACE2; ADAM-17; Angiotensin receptor blockers; Antiandrogens; COVID-19; Calmodulin antagonists; Camostat mesylate; Inhaled corticosteroids; Nafamostat mesylate; SARS-CoV-2; SERMs; TMPRSS2.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
The ACE2/TMPRSS2 pathway and its interaction with SARS-CoV-2. SARS-CoV-2 binds to membrane-bound ACE2 to enter the host cells. This interaction with ACE2 is mediated via the spike glycoprotein on SARS-CoV-2 surface. Spike protein priming is essential for entry of SARS-CoV-2 and relies upon TMPRSS2. The ectodomain of ACE2 can be shed by ADAM-17 generating the soluble form of ACE2 (sACE2). CALM interacts with ACE2 and inhibits shedding of its ectodomain. AR activation up-regulates TMPRSS2 expression, whereas ER activation potentially regulates ACE2 expression. Upregulation is represented by green. Potential up- or down-regulation is represented by orange. AR, androgen receptor; ACE2, angiotensin-converting enzyme 2; ADAM-17, disintegrin metalloproteinase 17; CALM, calmodulin; ERs, oestrogen receptors; sACE2, soluble ACE2; TMPRSS2, transmembrane protease, serine 2
Fig. 2
Fig. 2
COVID-19 early stage pharmacologic intervention targeting Sars-CoV-2 cell entry through the ACE2/TMPRSS2 pathway. Mechanisms of action of pharmacologic agents acting on the ACE2/TMPRSS2 pathway that could prevent Sars-CoV-2 entry to host cell are summarized. These agents include (i) directly acting agents such as hrsACE2 that imitates the soluble human enzyme ACE2; (ii) indirect ACE2 modulators including (a) ARBs that potentially block the binding and hence, attachment of SARS-CoV-2 to ACE2-expressing cells, (b) calmodulin antagonists that inhibit CALM-ACE2 interaction and increase the release of the ACE2 ectodomain, and (c) SERMs that potentially modulate ACE2 expression; (iii) TMPRSS2 inhibitors (camostat mesylate, nafamostat mesylate, antiandrogens, and potentially ICS if verified in different studies) that inhibit the S-mediated membrane fusion of SARS-CoV-2; and (iv) ADAM-17 enhancers (conjugated estrogens, 5-fluorouracil) that activate ADAM-17 and increase the release of the sACE2 through ACE2 ectodomain shedding. Upregulation is represented by green. Potential up- or down-regulation is represented by orange. Inhibition is represented by ⊣. AR, androgen receptor; ACE2, angiotensin-converting enzyme 2; ADAM-17, disintegrin metalloproteinase 17; ARBs, angiotensin receptor blockers; CALM, calmodulin; ERs, oestrogen receptors; ICS, inhaled corticosteroids; TMPRSS2, transmembrane protease, serine 2; SERMs, selective oestrogen receptor modulators; 5-FU, 5-fluorouracil

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