Dominance Of SARS-CoV-2 D614G Variant Explained By The Requirement Of COVID-19 For Calcium; Proximate Therapeutic Implication(S) For COVID-19

Abstract

The current dominance of D614G mutation in the SARS-CoV-2 pandemic implies increased infectivity of the virus S protein that drives cellular entry which is triggered by binding to the angiotensin converting enzyme-2 (ACE2) receptor and calcium-dependent protease-mediated activation. Understanding how the D614G spike protein mutation could produce a fitness advantage is key to therapeutic development given its epidemiological dominance. A 14-amino acid (aa) consensus sequence was found in 84 SARS-CoV-2 D614G entries from the NCBI Protein database. No other significant similarity to the D614G mutant sequence was found. A homology to the analogous wild type 14-aa consensus peptide was found in bat coronavirus (APO40579.1) and a smaller 13-aa consensus homology was found with SARS-CoV (AAP41037.1). A successive substring search constrained by the boundary of the D614G consensus peptide compared to all of the proteins in the unbiased Prosite EF-hand calcium-binding domain profile (PS50222) was undertaken because calcium triggers the protease-mediated activation of membrane fusion. A homology to single protein was found; a probable voltage-dependent N-type calcium channel subunit alpha-1B that is involved in the pore-forming regulation of transmembrane calcium transport (Uni Prot KB-P56698). A subsequent brute force Pub Med searching revealed the existence of a laboratory created aspartic acid to glycine mutation in the F protein human parainfluenza virus (hPIV-3 D104G mutation) that facilitated the spread of hPIV-3 in SPCA1 deficient cells. In humans, (SPCA1) regulates the Golgi luminal Ca2+ homeostasis and is ubiquitously expressed in all issues. Decreased SPCA1 expression causes Hailey-Hailey disease, a rare skin disorder that impairs a cells’ ability to transport Ca2+ (i.e., human ATP2C1 gene). Clinically the hypocalcemia associated with hospitalized COVID-19 patients can effectively impair Ca2+ transport in an analogous manner to the SPCA1 deficiency. Here, the D614G SAR-CoV-2 mutant strain can make use of clinical hypocalcemia like the D104G mutated hPIV-3 virus takes advantage of SPCA1 deficient cells to increase infectivity. These data demonstrate the critical importance of calcium for effective SARS-CoV-2/COVID-19 infection and how understanding this mechanism can be exploited for therapeutic gain to stop, or otherwise attenuate virus infection at the earliest steps. Calcium chelation by pharmaceutical EDTA, has been, and can be safely delivered via nebulizer or oral ingestion. EDTA treatment is available in outpatient and inpatient settings and can be self-administered during “quarantine” periods. These proven and safe EDTA treatments should effectively disrupt SARS-CoV-2 spread at the earliest step in the virus lifecycle and warrant investigation and optimization to save lives post haste.