*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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