Some researchers have claimed that Hydroxychloroquine (HCQ) can enter cells and make the environment more "alkaline" by soaking up protons. Many publications discuss only 2 nitrogen atoms that can accept a proton, however the molecule possesses 3, and therefore I would be interested to learn about the transport of HCQ, which is in the diacid form in the commercial Sulfate compound, is potentially in a triacid form in the stomach and is known to be predominantly in the diacid form in Blood at pH 7.4.
There is research demonstrating that the acid form is hydrophobic, compared to the neutral compound, which accounts for its much lower activity against Plasmodium, in which the neutral compound is lipophylic.
How many molecules of HCQ per cell have been found in clinical settings, and would this have any real impact on internal pH compared to natural buffers?
The environment that's supposed to be made more alkaline is only the endosomal compartment, not the entire cell or body. Naturally, endosomes slowly become more acidic, on their way to becoming lysosomes. Many viruses sense this acidification, and use it as a trigger to fire their endosome escape functions and enter the cytoplasm. If this fails, the virus will likely be destroyed once the lysosomes become mature and loaded with protease & RNAse.
To prevent endosome acidification, a traditional chemical buffering system is likely not the correct mechanism. This would more likely be achieved by a specific phamacological mechanism, like interrupting membrane integrity or inhibiting a proton transporter. I have seen remarkably little work on this, and all of it only in cell culture.
Thanks John Schloendorn I found an interesting paper on the protonation of Hydroxychloroquine and lysosomes here
Article Hydroxychloroquine is much less active than chloroquine agai...
Hi John, Can I ask you a question that has always bothered me? I got my degree over 40 years ago, and your knowledge on this is probably exponent factors above mine. Why is everyone talking about chemicals that have many competitively competing stereoisomers, with probably less than 10% of the required one available. Why not use quinine, which is 100% the correct enantiomer, 10 times the potency with much lower safer dose (20mg) prophylactically. Let me know. Thanks, stay safe.
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