The Repurposed ACE2 Inhibitors: SARS-CoV-2 Entry Blockers of Covid-19

Abstract

The highly infectious disease COVID-19 is induced by SARS-coronavirus 2 (SARS-CoV-2), which has spread rapidly around the globe and was announced as a pandemic by the World Health Organization (WHO) in March 2020. SARS-CoV-2 binds to the host cell's angiotensin converting enzyme 2 (ACE2) receptor through the viral surface spike glycoprotein (S-protein). ACE2 is expressed in the oral mucosa and can therefore constitute an essential route for entry of SARS-CoV-2 into hosts through the tongue and lung epithelial cells. At present, no effective treatments for SARS-CoV-2 are yet in place. Blocking entry of the virus by inhibiting ACE2 is more advantageous than inhibiting the subsequent stages of the SARS-CoV-2 life cycle. Based on current published evidence, we have summarized the different in silico based studies and repurposing of anti-viral drugs to target ACE2, SARS-CoV-2 S-Protein: ACE2 and SARS-CoV-2 S-RBD: ACE2. This review will be useful to researchers looking to effectively recognize and deal with SARS-CoV-2, and in the development of repurposed ACE2 inhibitors against COVID-19.) • COVID-19 Abbreviations CoV Coronavirus + ssRNA Single-stranded RNA ICTV International Committee on Taxonomy of Viruses SARS severe acute respiratory syndrome SARS-CoV 1 Severe acute respiratory syndrome coronavirus 1 This article is part of the Topical Collection ''Antiviral Drug Research''; edited by Guangxin Liang, Zheng Yin.

A Peek into Pandora’s Box: COVID-19 and Neurodegeneration

“…Significant expression levels of ACE2, CD147, and serine protease TMPRSS2 were detected in human and mouse brain cell lines, and in different brain regions of mice [ 142 ]. It is of interest to note here that several previously identified ACE2 inhibitors are currently being repurposed to treat COVID-19 and need further verification from clinical trials regarding their efficacy [ 143 ]. However, it is yet to be conclusively determined whether or not patients with hypertension and other cardiovascular comorbidities on long-term therapy with ACE inhibitors or angiotensin receptor blockers (ARBs) are at higher risk of poor outcomes from COVID-19 [ 144 , 145 , 146 ].…”

“…The therapeutic potential of thymoquinone, a component of Nigella sativa , against COVID-19 is worthy of further investigation due to multiple evidence of this compound’s efficacy in targeting the AMPK/PPARγ/PGC-1α and Nrf2/heme oxygenase (HO-1) pathway and in preventing SARS-CoV-2 entry into the cells [ 256 , 257 , 258 ]. Moreover, several plant-based compounds have antimicrobial activities, and some of the polyphenolic compounds, including flavonoids, terpenoids, hydrolysable tannins, etc., have potential inhibitory properties against ACE2 receptors [ 143 , 259 ]. Using molecular docking analysis, bioactive ligands were identified from medicinal plants that inhibited SARS-CoV-2 viral replication and transcription [ 260 , 261 ].…”

Small molecules in the treatment of COVID-19

“… 118 – 120 It was thought that targeting the virus entry process is more advantageous than targeting the subsequent stages of the SARS-CoV-2 lifecycle, thus many efforts have been made to find inhibitors blocking this process. 121 – 123 Small molecules targeting the S protein, ACE2, and the S protein–ACE2 complex were found to potentially inhibit SARS-CoV-2 infection. 124 , 125 The SARS-CoV-2 S protein consists of two subunits; S1 comprises the receptor binding domain (RBD) and S2 is responsible for viral membrane fusion.…”

“… 128 , 156 , 157 This cleavage is performed by host cells proteases, including serine protease transmembrane protease, serine 2 (TMPRSS2), cysteine protease cathepsin L (CTSL), and the arginine protease furin. 54 , 121 , 158 TMPRSS2 was thought to play an essential role in SARS-CoV-2 viral entry. 159 – 161 It enables rapid endosome-independent virus entry of SARS-CoV-2 into the cells (within 10 min).…”

Anti-Fungal Drug Anidulafungin Inhibits SARS-CoV-2 Spike-Induced Syncytia Formation by Targeting ACE2-Spike Protein Interaction

“…Several groups have conducted computational studies as well as experiments to study the interactions involving S protein and the ACE2 receptor. To target and disrupt the interactions by exploring repurposed drugs or novel inhibitors, attempts have been made to design ligands targeting S protein (Xiu et al, 2020;Wang et al, 2021) as well as ACE2 receptors (Ahmad et al, 2021). Despite the availability of several vaccines to treat COVID-19 and reduce the viral spread and disease severity, COVID-19 still requires novel therapeutics to fight the newly emerging SARS-CoV-2 variants and overcome the significant limitations in vaccine production and distribution, which hamper worldwide effective immunization.…”