key: cord-0944587-zut4wgxf
authors: Brogi, Simone; Calderone, Vincenzo
title: Off‐target ACE2 ligands: Possible therapeutic option for CoVid‐19?
date: 2020-05-13
journal: Br J Clin Pharmacol
DOI: 10.1111/bcp.14343
sha: 4985abe6f539db0b20ee742438312bcebb90d483
doc_id: 944587
cord_uid: zut4wgxf

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Herein, we wish to focus on an original pharmacological strategy, which has never been proposed until now: the targeting of ACE2 with "small-molecule" ligands, potentially able to induce conformational changes of ACE2 and thus to cause a possible reduction of the binding affinity between ACE2 and the viral spike protein. ACE2

(discovered in 2000) is an enzyme involved in the complex proteolytic pathway of the renin-angiotensin system (RAS). In the last two decades, ACE2 modulation has been considered as an appealing strategy for cardiovascular therapies. 8 This led to the design of novel chemical entities, such as-for instance-the "small-molecule" XNT, an ACE2-activator which was evaluated in preclinical studies as a promising cardiovascular drug. Noteworthy, the binding of XNT to ACE2 was found to abolish the protein-protein interaction between ACE2 and anti-ACE2 IgG autoantibodies of patients affected by autoimmune diseases, 9 indicating that the conformational changes induced by a "small-molecule" may effectively affect the binding affinity of ACE2 with ACE2-binding proteins.

Given the increasing interest towards ACE2 as a potential drug target, many drugs already approved by FDA for clinical use in heterogeneous human or veterinary diseases were evaluated, to identify a possible "off-target" ACE2-modulatory effects and thus to propose their "repositioning" in cardiovascular pathologies. 10 

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ACE2-activators has been reported.