PMC:7408073 / 66596-68825 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/7408073","sourcedb":"PMC","sourceid":"7408073","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7408073","text":"Of interest, a small cationic inhibitor of ACE2 (but not of ACE) has been detected in plasma samples [116]. The endogenous inhibitor might play a compensatory fine-control (within a threshold limit) for normal fluctuation of ACE2 protein in plasma and it has been hypothesized to be a basic AA or a small basic peptide able to compete with ACE2 substrates [116]. I have already mentioned that AA can chelate zinc forming labile zinc complexes of amino acids (see Box 4). It is therefore possible that a basic AA or a small basic peptide capable to specifically accommodate into the catalytic site of ACE2, but into that of ACE, could inhibit ACE2 activity. Indeed, despite the similarities, ACE and ACE2 possess different substrate specificity that depends on the smaller ACE2 binding pocket compared to that of ACE [90]. This specific aspect might determine the specificity for a specific basic amino acid or molecule that is able to accommodate into the catalytic pocket of ACE2 and bind to zinc. Among the possible endogenous ACE2 inhibitors, agmatine, decarboxylated arginine, has a chemical structure that resembles that of an ACE2 inhibitor, NAAE [127]. NAAE is a small molecule that had demonstrated an anti-SARS-CoV activity, by acting on both ACE2 catalytic activity and ACE2 binding domain for spike protein of SARS-CoV [127]. Unfortunately, NAAE has never been used in vivo. Indeed, NAAE is a weak ACE2 inhibitor, it is in fact more than a thousand-fold less potent than MLN-4760; however, if agmatine will be proven to have ACE2 inhibitory activity, it might be helpful to prevent the trigger of the positive feedback loops in the first mild phases of the disease. Indeed, it has an important role in down-regulating NO synthesis reducing NO overproduction by different mechanisms [128]. Of note, NOS pathway has been shown to be upregulated by both Ang (1–7)/MasR and Ang (1–9)/AT2 receptor pathways that are downstream ACE2 activity [38,39,41,43]. Moreover, agmatine has a regulated plasma concentration in the range of 20-80 ng/mL and the use of dietary agmatine has been shown to be safe and effective in reducing neuropathic pain [129]. Moreover, agmatine sulfate is regularly taken as a bodybuilding 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