1/12 PPIs and COVID19. Given interest in hydroxychloroquine (HCQ) and COVID19, and at least 1 major proposed mechanism of action (in vitro), I’ve be waiting for an obvious implication for prevention of COVID19 with a much safer OTC drug. @ToxAndHound @dereklowe

2/12 Not that I’ve seen any evidence that HCQ is effective, though it is good at causing TdP.
1st, HCQ is claimed to buffer protons in endosomes, raising endosomal pH. Will now keep things very simplified, mainly because I am a very simple person.

3/12 Vacuolar ATPases reside in the plasma membrane and are taken up into endosomes when the virus-ACE2 complex triggers endocytosis. Like all endosomes, pH rapidly falls to around 4.8 to 5.5 through action of this ATPase.

4/12 Simplistically, the drop in endosomal pH is required for release of viral genetic material, movement of virus through the cell, and viral propagation, in no particular order. This is similar to endocytosis of the transferrin receptor containing ferric iron.

5/12 The drop in pH causes the iron to dissociate, and the TfR is then returned to the plasma membrane. Back to COVID19 - members of the ATPase family are structurally similar, and we have one serving as the proton-K+ exchanger in gastric parietal cells.

6/12 If PPIs inhibit the gastric H+-K+ ATPase exchanger, might they also inhibit the vacuolar ATPase in endosomes, raising endosome pH? Of course they do. In cell cultures, PPIs can take endosomal pH from below 5 to the high 6s, approaching 7.0.

7/12 Lots of drugs become trapped in endosomes from low pH. PPIs have been used to raise endosomal pH to cause release of trapped endosomal chemotherapeutic agents in animals and cell cultures to restore sensitivity to chemotherapeutic drugs.

8/12 We’ve seen a run on HCQ (+/- azithro), and now ivermectin for COVID19. I would think that PPIs will be the next round of mass treatments without clinical trials, and I am hardly convinced they would be any more effective that HCQ, for which I see no convincing data.

9/12 But they would be a whole lot safer. Despite safety, they will come with drug interactions (e.g., inhibit 2C19, induce 1A2). If you take PPIs now, better quickly stock up, because I bet the shelves will be empty pretty quickly. Someone surely has thought of this.

10/12 And it gets more complicated. Various sentinel cells of our innate immune system and epithelial cells (including pneumocytes) express TLR7/8, which recognize ssRNA to trigger an immune response. Viral ssRNA bound to TLR7/8 is taken up into endosomes through endocytosis.

11/12 Endosome acidification promotes activation of the TLR to begin the cascade of events activating innate immune responses and secondary B cell responses down the line. Would a PPI also impair the immune response, as well?

12/12 And, are patients currently taking PPIs less likely to acquire COVID19? Are patients taking PPIs predisposed to other viral infections? Lots of questions. Lots of research has been done. Lots of research to do. Just wanted to get people thinking.
@ToxAndHound

Addressing oversimplification of processes involved, TLR7/8 are mainly expressed in endosomes, not on cell membranes. Endosomes containing virus in cytoplasm can fuse with other endosomes, some originating from the Golgi. Regardless, virus and TLR7/8 find themselves together.