Strategies for Targeting SARS CoV-2: Small Molecule Inhibitors-The Current Status

Abstract

Severe Acute Respiratory Syndrome-Corona Virus-2 (SARS-CoV-2) induced Coronavirus Disease - 19 (COVID-19) cases have been increasing at an alarming rate (7.4 million positive cases as on June 11 2020), causing high mortality (4,17,956 deaths as on June 11 2020) and economic loss (a 3.2% shrink in global economy in 2020) across 212 countries globally. The clinical manifestations of this disease are pneumonia, lung injury, inflammation, and severe acute respiratory syndrome (SARS). Currently, there is no vaccine or effective pharmacological agents available for the prevention/treatment of SARS-CoV2 infections. Moreover, development of a suitable vaccine is a challenging task due to antibody-dependent enhancement (ADE) and Th-2 immunopathology, which aggravates infection with SARS-CoV-2. Furthermore, the emerging SARS-CoV-2 strain exhibits several distinct genomic and structural patterns compared to other coronavirus strains, making the development of a suitable vaccine even more difficult. Therefore, the identification of novel small molecule inhibitors (NSMIs) that can interfere with viral entry or viral propagation is of special interest and is vital in managing already infected cases. SARS-CoV-2 infection is mediated by the binding of viral Spike proteins (S-protein) to human cells through a 2-step process, which involves Angiotensin Converting Enzyme-2 (ACE2) and Transmembrane Serine Protease (TMPRSS)-2. Therefore, the development of novel inhibitors of ACE2/TMPRSS2 is likely to be beneficial in combating SARS-CoV-2 infections. However, the usage of ACE-2 inhibitors to block the SARS-CoV-2 viral entry requires additional studies as there are conflicting findings and severe health complications reported for these inhibitors in patients. Hence, the current interest is shifted toward the development of NSMIs, which includes natural antiviral phytochemicals and Nrf-2 activators to manage a SARS-CoV-2 infection. It is imperative to investigate the efficacy of existing antiviral phytochemicals and Nrf-2 activators to mitigate the SARS-CoV-2-mediated oxidative stress. Therefore, in this review, we have reviewed structural features of SARS-CoV-2 with special emphasis on key molecular targets and their known modulators that can be considered for the development of NSMIs.

Keywords: COVID-19; NSMIs; SARS-CoV; SARS-CoV-2; natural Nrf-2 modulators.

Figure 1

The schematic representation of SARS-CoV-2 structure: SARS-CoV-2 has a size ranging from 60 to 140 nm, and is a spherical to elliptical shaped virus with a crown-like appearance; it consists of a single-stranded RNA genome, a Spike protein (S), a Matrix protein (M), a nucleoprotein (N), and an Envelope-protein (E).

Figure 2

Molecular pathogenesis of SARS-CoV-2 in human lung cells. Binding of S-protein of SARS-CoV-2 to the ACE-2 receptors triggers the processing of ACE-2 through ADAM-17/TNF-α-converting enzyme and induces the “ACE-2 shedding” into the extracellular space and facilitates uptake of SARS-CoV-2 followed by the development of SARS. Alternatively, the entry of SARS-CoV-2 by membrane TMPRSS2 serine protease'/HAT (Human Airway Trypsin-like protease)-mediated cleavage of ACE2 can facilitate SARS-CoV S-glycoprotein-mediated virus entry. Even though, several NSMIs targeting these processes were described and their mode of action against coronavirus were delineated, their efficacy against SARS-CoV-2 is yet to be tested.