*Full contact information for the corresponding autor:
Cardiology Department, Hospital La Luz, Madrid, Spain.
Address: Calle del Maestro Ángel Llorca, 8, 28003 Madrid, Spain
Telephone:+34 914530200.
E-mail: dr_garciaescobar@hotmail.com
Funding: None.
Congratulations to Calderone and Brogi for their letter regarding the off-target ACE2 ligands and approved drugs with possible off-target ACE2-modulatory effects.1
The angiotensin-converting enzyme 2 (ACE2) is a type I integral membrane protein (amino acids 805) that contains a transmembrane domain (amino acids 740-763) and extracellular region (ectodomain). The extracellular region is composed of a metalloprotease zinc-binding site (amino acids 374-378, HEMGH) that is the single catalytic domain of the ACE2, which is 42% identical to each of the two catalytic domains in angiotensin-converting enzyme (ACE), ACE functions as a dipeptidase whereas ACE2 as a carboxypeptidase.2,3 The ACE2 ectodomain undergoes shedding by a disintegrin and metalloproteinase domain‐containing protein 17 (ADAM17) also known as tumour necrosis factor alpha-converting enzyme, a protease up-regulated in heart failure (HF) consequently releases a soluble form of ACE2.4
Some studies have demonstrated that increasing soluble ACE2 levels are associated with HF, adverse cardiac remodelling and correlated with B-type natriuretic peptide levels.5,6,7 Hence, increasing soluble ACE2 activity indicates either an adaptive or maladaptive physiologic process operative in HF. 7
The spike protein (S) of severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) attaches the virus to its cellular receptor ACE2.8 Zhou P et al. demonstrated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) share 79.6% sequence identity to SARS-CoV-1 and uses the same cell entry receptor ACE2 and does not use other coronavirus receptors as aminopeptidase N or dipeptidyl peptidase.9 Similarly, Jia HP et al. showed the membrane-associated form of ACE2 serves as a SARS-CoV-1 receptor in vitro, and soluble ACE2 retains it is coronavirus receptor properties, furthermore identified a single mutation (ACE2-L584A) that prevented ACE2 shedding process.10 Structural analysis of ACE2 has revealed the presence of a single catalytic domain that is located in the ectodomain was identified as a functional receptor for SARS-CoV and the ectodomain is indispensable to viral attachment through a defined receptor-binding domain (RBD) on S mediates this interaction.11 Wang Q et al. demonstrated that S subunit 1 (S1) and the C-terminal domain of the SARS-CoV-2, otherwise known as the RBD, bound to soluble ectodomain protein of human ACE2 with 4-fold higher binding affinity compared with the SARS-CoV-1 receptor binding domain.12
Here are some strategies for targeting the ACE2 not mention before. Lei C, et al. constructed a fusion protein consisting of the extracellular domain of human ACE2 linked to the fragment crystallisable region (Fc) domain of human IgG1 (ACE2-Ig) and an ACE2 variant in which two active-site histidines have been altered to asparagines (mACE2-Ig), SARS-CoV and SARS-CoV-2 were neutralised in vitro with both recombinant ACE2.13 On the other hand, ACE2 activity is unaffected by 10 μM lisinopril, enalaprilat, or captopril, but activity was completely inhibited by 10 μM of calcium ethylenediaminetetraacetic acid (EDTA).14 This reinforces the proposition that ACE2 is a metalloprotease, but with a distinct substrate and inhibitor specificity from ACE. Therefore, chelating agents such as EDTA removes zinc, which is essential for activity and leads to complete inactivation. 3 g of EDTA IV weekly have shown a safety profile in patients with cardiovascular disease.15 It is know so far that the ACE2 ectodomain contains the a single catalytic domain composed of the metalloprotease zinc binding site (amino acids 374-378, HEMGH) and structural anaylisis have demonstrated that SARS-CoV-2 uses thise ectodomain for viral attachment, another potential therapeutic could be the disruption of the metalloprotease zinc binding site by the uses of chelator agent as EDTA with a low cost compared with many other treatments. Therefore this should be test in laboratory, in caso to prove the SARS-CoV-2 is neutralized in vitro, then a clinical trial should perform.
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