What Role Does the Angiotensin Converting Enzyme-2 Receptor Play in the Pathogenesis of the Novel Severe Acute Respiratory Syndrome-like Coronavirus (COVID19) Disease: A Systematic Review of the Literature

Abstract

The current COVID-19 pandemic represents the most significant infectious disease problem of recent times with rapid human to human transmission of SARS-CoV-2 that has affected numerous populations on a global scale and has resulted in marked morbidity, mortality and socioeconomic losses. A growing body of research has recognised that the human ACE-2 receptor is the primary site of SARS-CoV-2 binding, as well as that of its predecessor SARS-CoV-1, and thus, understanding the role of the receptor is imperative to eliciting the pathogenesis of COVID-19 disease and in the identification and development of therapeutic drugs and vaccines. This research aimed to summarise the role of the ACE-2 receptor for the former purposes by conducting a systemic review of relevant literature. Electronic databases of MEDLINE, EMBASE and the Cochrane library were search in August 2020 and articles were limited to English language and publication after the year 2000. Given the varied study designs, articles were appraised using a number of validated tools and the findings relevant to the research question were reported narratively. A total of 13 studies were eligible for inclusion, which comprised eight in vitro studies, four animal studies and one human trial. Quality/risk of bias varied from low to high. The evidence confirmed that the human ACE-2 receptor is the main site of SARS-CoV-2 targeting, which uses its surface S protein and specifically its subunit 1, to fuse and gain entry in host cells. Notably, the results demonstrated that SARS-CoV-2 can bind to human ACE-2 with much greater affinity than SARS-CoV-1, which correlated with greater infectivity and invasion of respiratory system cells. In regard to the role of the ACE-2 receptor, the receptor exerts a protective effect against lung injury as a result of antagonising ACE-mediated increases in angiotensin II. Thus, therapeutic options should focus upon developing ACE-2 receptor agonists and/or ACE-2 homologues, which in theory, could provide at least some protection against SARS-CoV-2 entry in human cells and the severity of COVID-19 disease that could lead to improvements in morbidity and mortality. Only one study reported preliminary phase one results regarding a serine protease inhibitor that targets the interaction between SARS-CoV-2 and ACE-2, which provided a desirable safety profile, although efficacy data is awaited in phase 2/3 trials. Vaccines targeting the same locus are also underway but again, results are awaited. Given the deleterious nature of angiotensin II in COVID-19 disease, it is recommended that ACE-inhibitors are avoided in infected patients. As a means to tackling the pandemic, 7 research and drug/vaccine developers should focus upon optimising ACE-2 actions and viral fusion to the receptor.