Inhibition of SARS-CoV-2 Entry into Host Cells Using Small Molecules

Abstract

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), a virus belonging to the Coronavirus family, is now known to cause Coronavirus Disease (Covid-19) which was first recognized in December 2019. Covid-19 leads to respiratory illnesses ranging from mild infections to pneumonia and lung failure. Strikingly, within a few months of its first report, Covid-19 has spread worldwide at an exceptionally high speed and it has caused enormous human casualties. As yet, there is no specific treatment for Covid-19. Designing inhibitory drugs that can interfere with the viral entry process constitutes one of the main preventative therapies that could combat SARS-CoV-2 infection at an early stage. In this review, we provide a brief introduction of the main features of coronaviruses, discuss the entering mechanism of SARS-CoV-2 into human host cells and review small molecules that inhibit SARS-CoV-2 entry into host cells. Specifically, we focus on small molecules, identified by experimental validation and/or computational prediction, that target the SARS-CoV-2 spike protein, human angiotensin converting enzyme 2 (ACE2) receptor and the different host cell proteases that activate viral fusion. Given the persistent rise in Covid-19 cases to date, efforts should be directed towards validating the therapeutic effectiveness of these identified small molecule inhibitors.

Geraniin Inhibits the Entry of SARS-CoV-2 by Blocking the Interaction between Spike Protein RBD and Human ACE2 Receptor

“…SARS-CoV-2 entry into cells occurs in three steps: (1) binding of SARS-CoV-2 to epithelial cells, (2) activation of spike protein by proteolysis, and (3) spike-mediated fusion [4,8,31]. Because SARS-CoV-2 binding results in interaction between the spike protein and hACE2 receptor, many studies are focusing on the development of small molecule-or peptide/antibody-based inhibitors that target the spike protein or hACE2 receptor [8,32]. Currently, several neutralizing antibodies against spike protein RBD have been developed and granted emergency use authorization for COVID-19 treatment by the U.S. Food and Drug Administration: regdanvimab (Celltrion Healthcare, Inc., Incheon, Korea), casirivimab and imdevimab cocktail (Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA), and bamlanivimab and etesevimab cocktail (Eli Lilly and Company, Indianapolis, IN, USA).…”

“…Currently, several neutralizing antibodies against spike protein RBD have been developed and granted emergency use authorization for COVID-19 treatment by the U.S. Food and Drug Administration: regdanvimab (Celltrion Healthcare, Inc., Incheon, Korea), casirivimab and imdevimab cocktail (Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA), and bamlanivimab and etesevimab cocktail (Eli Lilly and Company, Indianapolis, IN, USA). Small molecule-based inhibitors have also been intensively studied because their use is preferential in terms of stability, pharmacokinetics, and administration [32][33][34].…”

Computational and experimental insights on the interaction of artemisinin, dihydroartemisinin and chloroquine with SARS-CoV-2 spike protein receptor-binding domain (RBD)

“…Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein (S) mediates cellular invasion by interfering with angiotensin-converting enzyme 2 (ACE2) through its receptor-binding domain (RBD, residues 331-524 of S1 subunit, Figure 1A) (Tai et al 2020;Wrapp et al 2020). Targeting this assembly with small molecules, peptides and antibodies emerged as a possible intervention strategy to contrast infection (Al Adem et al 2020;Xiu et al 2020;Chen et al 2021). The antimalarial agent chloroquine is thought to be active against SARS-CoV-2 through a combination of mechanisms, such as the inhibition endocytic pathways by elevation of endosomal pH and the interference with glycosylation of ACE2 (Vincent et al 2005;Mauthe et al 2018;Gendrot et al 2020).…”

Perspectives on electrochemical biosensing of COVID-19

“…A single and positive-stranded RNA virus [ 1 ] (SARS-CoV-2) has infected people and caused deaths worldwide [ 2 ]. To date, more than 173 M people have been infected, resulting in >3.7 M death ( https://www.worldometers.info/coronavirus/coronavirus-cases/accessed 6.6.21 ).…”

“…The smallest E protein (∼8–12 kDa, 76 AA) is involved in viral budding and assembly, directing protein-protein interceptions and inducing membrane curvature, and preventing M protein aggregation. Based on its binding to the RNA genome, the N protein participates in viral assembly and budding [ 2 ]. The N protein is the most immunogenic viral structural protein that is shed just a few days after infection with a peak at around 10 days post-infection.…”