SARS-CoV-2: Origin, Evolution, and Targeting Inhibition

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused an outbreak in Wuhan city, China and quickly spread worldwide. Currently, there are no specific drugs or antibodies that claim to cure severe acute respiratory diseases. For SARS-CoV-2, the spike (S) protein recognizes and binds to the angiotensin converting enzyme 2 (ACE2) receptor, allowing viral RNA to enter the host cell. The main protease (Mpro) is involved in the proteolytic process for mature non-structural proteins, and RNA-dependent RNA polymerase (RdRp) is responsible for the viral genome replication and transcription processes. Owing to the pivotal physiological roles in viral invasion and replication, S protein, Mpro, RdRp are regarded as the main therapeutic targets for coronavirus disease 2019 (COVID-19). In this review, we carried out an evolutionary analysis of SARS-CoV-2 in comparison with other mammal-infecting coronaviruses that have sprung up in the past few decades and described the pathogenic mechanism of SARS-CoV-2. We displayed the structural details of S protein, Mpro, and RdRp, as well as their complex structures with different chemical inhibitors or antibodies. Structural comparisons showed that some neutralizing antibodies and small molecule inhibitors could inhibit S protein, Mpro, or RdRp. Moreover, we analyzed the structural differences between SARS-CoV-2 ancestral S protein and D614G mutant, which led to a second wave of infection during the recent pandemic. In this context, we outline the methods that might potentially help cure COVID-19 and provide a summary of effective chemical molecules and neutralizing antibodies.

Immunobiotic Lactobacilli Improve Resistance of Respiratory Epithelial Cells to SARS-CoV-2 Infection

“…The genetically diverse Orthocoronavirinae family circulates in many species including avian and mammalian species. Three dangerous human coronaviruses (CoV) have emerged in the past 20 years: severe acute respiratory syndrome CoV (SARS-CoV) in 2002, Middle East respiratory syndrome CoV (MERS-CoV) in 2012, and SARS-CoV-2 in 2019, which is the causal agent of coronavirus disease 2019 (COVID-19) that has affected global health during 2020 and 2021 [ 1 ]. A significant proportion of SARS-CoV-2-infected persons are asymptomatic, while clinical symptoms of COVID-19 range from relatively mild common cold-like illness such as cough, fever, myalgia and fatigue, to severe dyspnea, chest pain, multifocal pneumonia, acute respiratory distress syndrome (ARDS), and multi-organ dysfunction syndrome [ 2 ].…”

The effect of various compounds on the COVID mechanisms, from chemical to molecular aspects

“…This pyrophosphate may obstruct nucleotide three phosphates (NTP) entry into the active site by occupying the nucleotide input. The 10-cyano substituent of incorporated RDV sterically clashed with the side chain of serine 861, which inhibits the chain termination reaction [ 145 ].…”

“…RMP interacts with the upstream bases from the primer chains to form base stacking and forms two hydrogen bonds with the uridine groups from the template chains [ 145 ]. Thus, it seems that modifying the structures to make phosphate more favorable for covalent incorporation at the extending strand terminus and designing some analogous pyrophosphate bound with other functionalities such as fluorine functional groups to improve its hydrogen bond acceptivity can cause the compounds to interact with RdRp more favourably.…”

The sense of taste: Development, regeneration, and dysfunction

“…To date, the mechanism(s) by which SARS-CoV-2 causes taste loss is unknown, but current hypotheses and limited data support an impact of the virus at the level of the lingual epithelium, for example, Cooper et al, 2020;Mastrangelo et al, 2021. The spike (S) protein of SARS-Cov-2 binds the ACE2 transmembrane protein and combined with S-protein cleavage by serine proteases such as TMPRSS2 and Furins, allows infection of host cells. ACE2 is a key enzyme in the reninangiotensin-aldosterone system (RAAS), which regulates blood volume by controlling sodium and water balance (see Ning et al, 2021). While RAAS peptides, receptors, and enzymes have been shown to be expressed by type II sweet/ umami-sensing and salt-sensing TRCs in mice (Shigemura et al, 2019), ACE2 protein expression in taste buds had not been reported.…”