The worldwide spread of catastrophic coronavirus 2019 (COVID-19) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, infected 2.3 million people and 160,000 deaths causing massive disruption to social, economic, and public healthcare systems [1–2]. Until now, seven endemic human corona viruses (HCoV)-OC43, 229E, HKU1and NL63 have been documented to cause mild respiratory tract infections. Over the past two decades, the world has witnessed viral epidemics such as severe acute respiratory (SARS-CoV), H5N1 influenza A, H1N1, and Middle East respiratory syndrome (MERS-CoV) causing acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) [3–5].
SARS-CoV-2, the novel beta-corona virus responsible for the COVID-19 pandemic, originated in Wuhan, China has emerged as a lethal infection. The genomic sequence of SARS-CoV-2 shares 96% of similarity with a bat corona virus RaTG13, which is highly remarkable, suspecting bats to be the most probable source of zoonotic infection [6–7]. The genome of SARS-CoV-2(30 kb in size) is an enveloped, non-segmented, positive-single-stranded RNA, which encodes two Open Reading Frames (ORFs) represented as ORF 1a and 1b which is the largest gene in the downstream region coding for non-structural proteins (Nsp) such as proteases (3CLpro and PLpro), RNA-dependent RNA polymerase (RdRp), helicases and other accessory proteins involved in viral replication and assembly in the host cell. Moreover, it encodes for four structural proteins such as spike (S), envelope (E), membrane (M), and nucleocapsid (N) glycoproteins (GPS) [8–11]. Importantly, the transmembrane S protein of SARS-CoV-2 exploits host angiotensin-converting enzyme 2 (ACE2) as the entry receptor, and the host cellular serine protease TMPRSS2 type-2 enzyme cleaves S protein into S1 and S2 subunits. Receptor-binding domain (RBD) in S1 binds to the extracellular N-terminus or protease domain (PD) of the full-length ACE2 receptor, while the S2 endo C-terminus region facilitates the fusion of the viral and cellular membranes, resulting in the SARS-CoV-2 entry and replication in the target cells as shown in Fig. 1 [12–13]. The S protein's RBD 3-D structure in SARS-CoV-2 is like SARS-CoV except for a few amino acid variations at key residues, exhibiting strong interaction and higher binding affinity with ACE2 as compared to SARS-CoV in humans and bats [14–17].
ACE2 receptor is a carboxy peptidase enzyme. In humans, it is widely expressed in various organs/tissues including the kidney, heart, and intestines. It is also enriched in the lung alveolar type 2 (AT2) cells [18]. Physiologically, ACE2 regulates the renin-angiotensin system (RAS) signalling pathway and converts angiotensin I and II into angiotensin 1–9, and angiotensin 1–7. Ang 1–7 is the key product of ACE2 that binds to the G-coupled Mas receptor (MasR), which is known to safeguard cardiovascular functions via mechanisms including vasodilation and controls endothelial permeability. [19]. Primarily, SARS-CoV-2 infection occurs in mucosal cells and spreads to AT2 cells inhibiting ACE2 expression and therefore disrupting the RAS pathway which is likely to be involved in the pathogenesis of ARDS and acute lung injury (ALI), further leading to extensive inflammation [20]. Knock out of the ACE2 receptor in mice after experimental SARS-CoV infection significantly reduced its replication and infection. Hence, it indicates that the interaction of the SARS-CoV-S protein with ACE2 is critical for the pathogenesis of SARs-CoV infection [21]. Different classes of in-vitro-tested drugs like remdesivir, favipiravir (FPV), darunavir, ritonavir, hydroxychloroquine, teicoplanin, nitazoxanide, chloroquine, and tocilizumab have shown their activity against Covid-19 infection.
To date, there are no suitable drugs devised against SARS-CoV2 infection, clinicians and scientists are still exploring the best pharmacotherapeutic strategies. Hence, it is indicative that there is an urgent need for the development of new anti-Covid-19 drugs. Drug repurposing has emerged as a promising strategy and is defined as the process of generating an innovative pharmacological approach for existing, approved drugs. Comparatively, repurposed drugs not only reduce the duration for optimization of chemical compounds but also cut off the cost of testing the toxicity of the compounds, as when compared to the discovery of de novo drugs [22–26]. Furthermore, non-structural proteins of SARS-CoV-2 like RNA-dependent RNA polymerase (RdRp) and main protease (Mpro) are being targeted to discover vaccines against Covid-19 [27].
The study emphasizes the role of ACE2 as a potential therapeutic target for finding new treatment strategies to prevent Covid-19 infection and transmission. Provisionally, full-length ACE2 inhibitors as small molecules or compounds can serve as a novel therapeutic approach that blocks SARS-CoV-2-S protein-mediated cell fusion to prevent its entry into the target cells.