Does Covera-19 know ‘when to hold ‘em or ‘when to fold ‘em? A translational thought experiment

Abstract

The function of proteins depends on their structure. The structural integrity of proteins is dynamic and depends on interacting nearby neighboring moieties that influence their properties and induce folding and structural changes. The conformational changes induced by these nearby neighbors in the micro-environmental milieu at that moment are guided by chemical or electrical bonding attractions.There are few literature references that describe the potential for environmental milieu changes to disfavor SARS-CoV-2 attachment to a receptor for survival outside of a host. There are many studies on the effects of pH (acid and base balance) supporting its importance for protein structure and function, but few focus on pH role in extracellular or intracellular protein or actionable requirements of Covera-19.‘Fold ‘em or Hold ‘em’ is seen by the various functions and effects of furin as it seeks an acidic milieu for action or compatible amino acid sequences which is currently aided by its histidine component and the structural changes of proteins as they enter or exit the host. Questions throughout the text are posed to focus on current thoughts as reviewing applicable COVID-19 translational research science in order to understand the complexities of Covid-19.The pH needs of COVID-19 players and its journey through the human host and environment as well as some efficacious readily available repurposed drugs and out-of-the box and easily available treatments are reviewed.

Expression profiles of respiratory V-ATPase and calprotectin in SARS-CoV-2 infection

“…The physiological stable pH around 7.4 is critical for the dependence of proteins that are charged macromolecules, abnormal regulation of which would impair many cell functions [ 21 ]. Intra- and extra-cellular pH may influence the entry of SARS-CoV-2, and Niclosamide, which can change the intracellular pH value has been considered as a candidate for COVID-19 treatment [ 7 , 22 ]. S protein could decrease the intracellular/lysosome pH value in our wet experiment, whereas had no obvious effects on extracellular pH, possibly for the powerful buffer system in culture medium (data not shown).…”

“…Compared with other coronavirus, SARS-CoV-2 has higher rates of transmissibility due to the insertion of furin site in spike (S) protein [ 4 – 6 ]. It has been reported that the acidic microenvironment is mainly created by vacuolar-ATPase (V-ATPase), which is necessary for furin to be active in cellular lysosomes, as well as fusion process of SARS-CoV-2 and host membranes [ 7 – 9 ]. Recent genome-wide CRISPR-Cas9 screens have identified V-ATPase subunits as SARS-CoV-2 cofactors [ 10 – 12 ], among which V1 peripheral domain is composed of 8 subunits (A-H), which drives ATP hydrolysis to energize and triggers the rotation of the V0 membrane domain, whereas the latter is composed of a, c, c˝, d, and e subunits, which utilizes the energy generated by the V1 domain to translocate protons across the membrane [ 13 , 14 ].…”