PMC:7556165 / 68370-72722 JSONTXT

{"target":"http://pubannotation.org/docs/sourcedb/PMC/sourceid/7556165","sourcedb":"PMC","sourceid":"7556165","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7556165","text":"ACE2 as a Therapeutic Target\nAs evidence builds up, ACE2 rapidly emerged as a specific target for COVID-19 treatment. Since this enzyme was identified as the SARS-CoV-2 receptor (Zhou et al., 2020), several approaches to address ACE2 mediated infection have been described (Li Y. et al., 2020; Zhang H. et al., 2020), with the aim to prevent host cell entry and subsequent viral replication, as well as severe lung injury. Potential therapeutic approaches include (Figure 10):\nFIGURE 10 Schematic representation of the potential therapeutic approaches to address ACE2 mediated infection. Exogenous administration of soluble recombinant human ACE 2 sequesters circulating viral particles, while specific ACE2 blockers bind the receptor, impeding the S-protein interaction with the host target. 1. ACE2 blockers;\n2. Exogenous administration of ACE2.\n\nACE2 Blockers\nBlockade of ACE2 receptor could be achieved through specific antibodies (Li et al., 2003), rationally designed small molecules (Dales et al., 2002; Huentelman et al., 2004; Gross et al., 2020; Pillaiyar et al., 2020) or peptides (Huang et al., 2003). Although their efficacy needs to be confirmed, some of these agents are currently available on the market and have been show to effectively block SARS-CoV invasion (Li S.-R. et al., 2020). For instance, the small synthetic inhibitor N-(2-aminoethyl)-1aziridine-ethanamine (NAAE) binds ACE2 active site in its closed conformation; this contact triggers the shifting of SARS-CoV S binding residues preventing the molecular interaction with targeted enzyme and the subsequent cell-cell fusion (Huentelman et al., 2004). Therefore, although ACE2 catalytic site is distinct from the S-protein-binding domain, NAAE exerts dual inhibitory effects on ACE2 catalytic activity and SARS binding (Adedeji and Sarafianos, 2014). However, since a protecting role for ACE2 receptor against virus-induced acute lung injury in infections with SARS coronavirus has not been excluded (Imai et al., 2005; Kuba et al., 2005; Li S.-R. et al., 2020), the choice of ACE2 inhibition as therapeutic approach should be carefully evaluated.\n\nExogenous Administration of ACE2\nThe administration of a large amount of soluble form of ACE2 could represent an intriguing opportunity, since excessive ACE2 may exert dual functions: (a) competitively bind SARS-CoV-2 to neutralize the virus and/or slow viral entry in the host cell; (b) rescue cellular ACE2 activity, which negatively regulates RAAS and may theoretically exert a protective effect in lung injury (Verdecchia et al., 2020a). A pilot clinical study is currently investigating the efficiency of a recombinant human angiotensin-converting enzyme 2 (rhACE2) in patients with COVID-19 (Zhang H. et al., 2020).\nRecombinant human ACE 2, rhACE2 (hrsACE2, APN01, GSK2586881), sequesters circulating viral particles interfering with S-protein binding to its host target, beside its role in regulating the systemic RAAS. Taken together, these activities may offer therapeutic benefits in COVID-19 patients, although the large molecular weight of the protein may potentially limit its effects on local RAAS (Gheblawi et al., 2020). rhACE2 has already undergone phase 1 and 2 clinical trials in healthy volunteers and in a small cohort of patients with ARDS (Khan et al., 2017). Moreover, it has been demonstrated that rhACE2 can significantly block the early stages of SARS-CoV-2 infections in engineered human blood vessel organoids and human kidney organoids (Monteil et al., 2020). In this context, Procko (2020) was able to engineer hACE2 sequences to obtain soluble receptors able to sequester SARS-CoV-2 RBD and inhibit its cell attachment. Remarkably, combinatorial mutants enhanced ACE2 binding to SARS-CoV-2 RBD by an order of magnitude, as compared to the wild type receptor form, and targeted ACE2 mutations might provide further improvement.\nAdditionally, the availability of ACE2 nanoparticles applied to nose filters, chewing gums, clothes, filters and gloves could be of help in sequestering the virus thus preventing its entry into the host (Aydemir and Ulusu, 2020). Prevention virus transmission could represent a more convenient strategy than therapeutic interventions on viral infection, avoiding interference with ACE2 and disturbance of the finely regulated RAAS axis (Aydemir and Ulusu, 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