Thread by @markfmccarty

@Covid19Crusher

SARS-CoV-2 virions attach to the ACE2 membrane protein, then are taken into cells engulfed in endosomes. In order to break into the cytoplasm – where the virus can replicate – the lipid envelope of the virions must fuse with the endosomal membrane.

Cleavage of the viral spike protein by the enzyme cathepsin L is required for this fusion.

pubmed.ncbi.nlm.nih.gov/32221306/ pubmed.ncbi.nlm.nih.gov/32470470/

Cathepsin L’s activity is pH dependent; it’s optimal at the acidic pH that normally prevails in endosomes, but is inhibited at neutral or alkaline pH. Hence, endosomal alkalization can slow the ability of SARS-CoV-2 to spread from cell to cell.

pubmed.ncbi.nlm.nih.gov/3382672/

Both HCQ and AZM are lipophilic weak bases that can readily diffuse into endosomes, in which they rapidly become protonated, driving up endosomal pH and thereby suppressing Cathepsin L activity. In this protonated form, they are trapped in the endosome.

Further, as proposed by Scherrmann, AZM can be actively transported into endosomes via the ABCB1 transporter, further enhancing its alkalinizing effect.

. pubmed.ncbi.nlm.nih.gov/32533263/

This likely explains why, in case series by Raoult and Guerin, patients receiving both drugs tended to do better clinically than those receiving only one – the degree of endosomal alkalinization achieved is more intense.

pubmed.ncbi.nlm.nih.gov/32205204/

That’s why we must press for controlled studies evaluating HCQ + AZM in early treatment – like the one that the NIH JUST CANCELLED.

https://twitter.com/markfmccarty/status/1274837596527452163

Cathepsin L activity can also be inhibited directly by the available antibiotic teicoplanin in clinically relevant concentrations.

pubmed.ncbi.nlm.nih.gov/32179150/

pubmed.ncbi.nlm.nih.gov/32454071/

I find the claim that zinc mediates the antiviral activity of HCQ to be doubtful. Normal cytoplasmic levels of free zinc are in the low nanomolar/high picomolar range – whereas zinc’s inhibition of viral protein synthesis in cell culture requires micromolar concentrations.

I doubt that HCQ, in vivo, could raise intracellular concentrations that high. Moreover, whereas chloroquine is a zinc ionophore, I can’t find evidence that HCQ is.

Nonetheless, zinc supplementation, especially in the elderly, has immunosupportive and anti-inflammatory effects that make it a very smart adjunct in COVID-19 therapy.

pubmed.ncbi.nlm.nih.gov/17344507/

Further, an observational study found that patients receiving HCQ/AZM/Zn did decidedly better than those receiving just HCQ/AZM – and Raoult’s group found that low serum Zn predicted poorer outcomes.

medrxiv.org/content/10.110…

Key: Treat with anti-viral measures as soon after onset of symptoms as feasible, to minimize spread of the virus so natural immunity can snuff it out before it colonizes most of the lung. Once most of the lungs are colonized, your immune response to the virus may snuff YOU out.

Anti-inflammatory measures are needed for late-stage disease.

The antiparasitic drug ivermectin, unlike HCQ/AZM, appears to be helpful in the late inflammatory stage of COVID-19. This likely reflects, not an anti-viral action, but a profound systemic anti-inflammatory effect.

. Modest doses of this drug can save mice from the septic shock induced by otherwise lethal doses of LPS.

medrxiv.org/content/10.110…

pubmed.ncbi.nlm.nih.gov/19109745/

Other available drugs, such as pentoxifylline, dipyridamole, low-dose corticosteroids, tocilizumab, and low-dose heparin appear to have potential for preventing/controlling cytokine storm and preventing thrombotic complications.

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