Hydroxychloroquine, SARS-COV-2, and pH
Hydroxychloroquine, SARS-COV-2, and pH. Citing randomized controlled trials on the efficacy of hydroxychloroquine as a treatment for COVID-19 is misleading as the mechanism of action would likely not support its use in the treatment of an active infection. Those RCTs referenced in the media used this medication in the treatment of patients with active disease.
A systematic review https://onlinelibrary.wiley.com/…/f…/10.1111/1756-185X.13842 on prophylactic hydroxychloroquine found no RCTs specifically evaluating the role of hydroxychloroquine as a prophylactic measure, however, there are five clinical trials pending enrollment (2 completed) to assess the prophylactic potential.
https://www.clinicaltrials.gov/ct2/show/NCT04303507 https://clinicaltrials.gov/ct2/show/NCT04318444 https://www.clinicaltrials.gov/ct2/show/NCT04318015 https://clinicaltrials.gov/ct2/show/NCT04304053 (completed enrollment) https://www.clinicaltrials.gov/ct2/show/NCT04308668 (completed enrollment)
It is likely incorrect to claim this is a cure based on the mechanism of action alone but has potential as a prophylactic agent. For those inclined, here are a few concepts/articles regarding pH and coronavirus. This is not medical advice.
1. To determine the pathway utilized by the SARS-CoV, the pH dependence of the SARS-CoV S-pseudotyped lentiviral vector (not SARS-CoV-2) was analyzed. Addition of ammonium chloride, which prevents acidification of the endosome, caused a dose-dependent reduction in viral entry at concentrations similar to those described for other pH-dependent viral glycoproteins. (like HIV) This effect was also observed with another inhibitor of endosomal acidification, bafilomycin, also in a dose-dependent fashion. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC415834/
2.Hydroxychloroquine accumulation in human organelles also raise their pH, which inhibits antigen processing, prevents the alpha and beta chains of the major histocompatibility complex (MHC) class II from dimerizing, inhibits antigen presentation of the cell, and reduces the inflammatory response. Elevated pH in the vesicles may alter the recycling of MHC complexes so that only the high affinity complexes are presented on the cell surface. Self peptides bind to MHC complexes with low affinity and so they will be less likely to be presented to autoimmune T cells. https://www.drugbank.ca/drugs/DB01611
3. Lysosomes contain many different kinds of digestive enzymes, and the inside of the lysosome is acidic, with a pH of around 5. The enzymes of the lysosome are specialized to perform their function only at this low pH; so, should they leak out into the cytosol, which has a pH of around 7.2, they do not do a great deal of damage. The inside of the lysosome is made acidic by the action of specialized transport proteins that lie in the lysosomal membrane and 'pump' hydrogen ions into its lumen. https://www.open.edu/…/sc…/tour-the-cell/content-section-4.9
4. Here we show that exogenous hydrogen peroxide (H2O2) induced lysosome depletion and recovery characteristic of autophagic lysosomal reformation, and we confirmed the occurrence of autophagic lysosomal reformation after H2O2 treatment by demonstrating Rab7 dissociation from autolysosomes, recruitment of Phosphatidylinositol 4-phosphate (PI4P) and clathrin to the surface of autolysosomes, and the existence of tubular “pro-lysosome” structures extending from autolysosomes. https://www.sciencedirect.com/…/a…/abs/pii/S1357272515300649
6. Rapamycin may have merit in improving lysosomal function.
7. Lysosomal function may be one of many of the key differentiators explaining the variation between pediatric and adult infectivity rates. A decline of lysosomal function occurs in the aged and those with certain diseases, whether it is the cause of aging or a manifestation thereof is not apparently known.
8. Subpopulation of GLP-1 agonist T2D patients might be evaluated for improving lysosomal function and reducing pulmonary inflammation/cytokine related damage only in the absence of severe renal disease. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5733334/
9.Further study of these SARS-CoV viroporins outside the complicated context of infection, especially their ability to induce pH changes in the lumen of the secretory pathway, will inform our studies on the IBV E protein.Our results are the first demonstration that the luminal microenvironment of the Golgi membrane is altered by coronavirus infection. While other viral viroporins (e.g., IAV M2 and HCV p7) have been shown to alter the luminal microenvironment, IBV E appears to do so by a mechanism that does not involve its ion channel activity. Whether the role of the putative IBV E-interacting protein(s) is pH maintenance, vesicle formation, membrane architecture, protein glycosylation, or any number of jobs performed by constituents of the secretory pathway, interaction of the protein(s) or lipid(s) with the large amount of IBV E known to reside at the ERGIC could disrupt the pH directly or indirectly by interfering with normal secretion or architecture of the Golgi complex. https://jvi.asm.org/content/93/11/e00015-19