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Zinc Ionophores To The Rescue
Recent Hypotheses By Thomas Hesselink, MD

Zinc comes in ionic form as Zn++. By virtue of its positive electric 
charge it is hydrophilic (attractive to water) and lipophobic 
(avoidant of lipids/oils). Therefore, if it is to pass through 
cellular membranes, which are loaded with lipids, the Zn++ must be 
modified. Molecules exist which can attach to Zn++ in such away that 
the overall electric charge of the product is neutral and the combination 
is much less lipophobic. Thus the modified Zn++ can pass more easily 
across a cell membrane. Such a molecule must have negatively charged 
reactive groups (such as carboxylate or sulfonate) or nucleophilic 
reactive groups (electron rich and positive charge seeking). Examples 
are thiols, amines or imidazoles. Such electron rich reactive groups 
are necessary to encourage attachment of the positively charged Zn++. 
The attaching molecule is usually called a "chelator" and its reaction 
product with the Zn++ is called a "zinc-chelate" or "chelated zinc". 
For any such zinc-chelate to be useful in this context it must be fairly 
stable under biologic conditions and survive the many different 
environments in a live body. However, this binding reaction must be 
reversible to enable the Zn++ to later be released from its chelating 
agent at sites where the Zn++ is needed. Numerous chelating agents 
already exist that will bind to Zn++. If they can also mobilize the 
Zn++ for passage through cellular membranes, then this process can be 
exploited to accomplish movement of Zn++ into cells (Zn++ influx). 
Such a chelator is termed an "ionophore". An ideal ionophore would 
be nontoxic both in its free form and in its zinc-chelated form. 

		Zn++ Inhibits Viral Replication 
Since Zn++ strongly inhibits RNA dependent RNA polymerase (RdRp) an 
enzyme which is absolutely necessary for the replication of RNA viruses 
including CoViD-19. Therefore it is critically necessary to discover and 
to utilize zinc-ionophores for the treatment of active corona infections. 
Of recent fame are chloroquine and hydroxychloroquine prescribed along 
with zinc for the successful treatment of active corona virus infection. 
This strategy inhibits viral replication and buys more time for the host 
immune system to develope neutralizing antibodies against the virus. 
If the virus succeeds in spreading to the lungs too rapidly, then the 
patient goes into severe acute respiratory distress syndrome. 
If a healthy rapid acting immune system can produce neutralizing 
antibodies quickly enough to deactivate the infection before it reaches 
the lungs then that patient will survive. If the immune system is slow 
or otherwise impaired it will lose this race against time and the 
patient will need artificial ventilation. 

		Calling For Additional Ionophores 		
Now given the rapid spread of CoViD-19 and the extensive numbers 
of severely infected people needing zinc-hydroxychloroquine therapy, 
this medicine is rapidly falling into short supply. Other zinc-ionophores 
worthy of our attention are now desperately needed. Upon extensive 
searching of the medical literature, the author has found several 
candidates, thanks to and the tireless efforts of thousands 
of diligent researchers. The following are offered to the reader 
as worthy candidates (with some disqualifiers) for clinical trials 
in active CoViD-19 cases. 

Generally speaking all acids are named conventionally in chemistry 
as "[name]ic acid". When the hydronium ion (H+) is replaced by another 
cation such as Na+ or Zn++ the name changes to "[name]ate". 
A "[name]ate" is also called the conjugate base of the original acid. 
If a cation is associated with only one molecule of conjugate base 
then the product is called "mono [name]ate". If two molecules of 
conjugate base are associated, it is called "bis [name]ate". 

Gluconic acid is a sugar acid which binds loosely to zinc to form 
zinc bis gluconate (ZnGluc2). It has been used extensively as an aid 
to enhance zinc absorption from oral dosing. In that regard it is 
superior to zinc sulfate. Since it is functioning as an effective 
ionophore, it should be useful to inhibit RdRp, if sufficient 
zinc is delivered to the infected cells. However since ZnGluc2 is 
large and bulky its progress may be slow. 

Glycine (the simplest amino acid) chelates and mobilizes zinc 
very well and could serve as an ionophore. It usually forms 
zinc bis glycinate (ZnGly2). Glycine has been shown to enhance 
absorption and utilization of zinc superior to sulfate or gluconate. 

Picolinic acid has been shown to attach to zinc and to mobilize 
it throughout the body. It naturally occurs in pancreatic juice, 
where it serves to enhance zinc absorption from the gut. However, 
in some models it accelerates urinary excretion, which should 
be easy to overcome by resupplying more zinc bis picolinate (ZnPic2) 

Nicotinic acid (also known as niacin or vitamin B3) is an isomer 
of picolinic acid and should provide similar ionophoric effects. 
The dose will probably not need be so high as to cause severe flushing. 

Citric acid in its citrate form binds and mobilizes zinc. 
Of all candidates this should be the easiest to obtain. 
One could theoretically drink lemonade with one's zinc pills. 
Another possible advantage is that citrate is rapidly metabolized, 
which would render zinc influx to be more long lasting. 
If the citrate disappears after delivering its zinc into the cell, 
then it cannot pull it back out after the payload is delivered. 

Salicylic acid chelates various cations including zinc and mobilizes 
them in some models. Zinc bis salicylate (ZnSal2) might therefore be 
able to reach and to penetrate viral infected cells. Salicylate also 
functions to downregulate inflamation, pain and fever, which is its 
long traditional purpose (welcome relief of the symptoms in any viral 
infection). Salicylate also quenches hydroxyl radical (HO*) protecting 
tissues from damage caused by this reactive oxygen species, which is 
produced in dangerous amounts during severe inflammation. Finally, 
salicylate induces enhanced activity of AMPK, which stimulates 
mitochondrial function. This in turn enables cells to produce more 
chemical energy. However, since salicylate tightly binds to zinc and 
forms an insoluble precipitate in vitro, it is not known how well ZnSal2 
might serve as an ionophore, nor if it would release Zn++ inside cells. 

			5-amino Salicylate 
5-aminosalicylic acid (5-ASA) is structurally very similar to 
salicylic acid with the addition of an amino group on carbon number 
5 of the aromatic ring. 5-ASA has long been used effectively to treat 
inflamation of the colon. Zinc bis 5-aminosalicylate (Zn5-ASA2) has 
in a few studies been shown to be quite mobile. It could theoretically 
serve as yet another effective antiRdRp ionophore for Zn++. 

Captopril (a generally safe ACE1 inhibitor used to treat high 
blood presssure) is an excellent binder and mobilizer of zinc. 
However, even if it successfully aids zinc influx, it just as 
readily carries the zinc back out and into the urine. By this 
mechanism captopril has been shown over periods of several months 
to induce zinc deficiency. Therefore, captopril theoretically is 
incompatible with zinc-ionophore therapy in cases of active 
corona virus infection. Captopril should be stopped temporarily 
and could be resumed once the infection has cleared. Nevertheless, 
captopril might still be useful as an ionophore for Zn++ if Zn++ 
is repeatedly replenished to make up for the lose to the urine. 

Taurine is an amine and a sulfonic acid. It has been shown to 
mobilize zinc in various models, even though some studies show 
enhanced excretion. Taurine is a safe nutritional metabolite and 
might prove to be another useful ionophore. So far there has been 
only a little published pertaining to the ionophoric capabilities 
of taurine. 

L-cysteine in numerous models has  been shown to be another 
excellent binder and mobilizer of zinc. Various enzymes that 
utilize zinc in the active center have cysteine residues which 
hold the zinc in catalytic position. Zinc bis cysteinate (ZnCys2) 
may be an excellent choice to nourish zinc deficient cells and 
to deliver Zn++ to corona virus infected cells. However, cysteine 
is an essential nutrient for construction of the spike-proteins 
of the corona virions. This presents a terrible dilemma, we may 
need cysteine to chelate and carry Zn++ to the infected cells, 
but then it could go on to nourish the viral construction process. 
Therefore, it is probably wise to defer the use of cysteine as 
an ionophore in favor of other ionophores. 

L-tryptophan enhances absorption and mobilization of Zn++. 
Therefore it also could serve as an antiviral ionophore except 
for the same dilemma. Tryptophan is also an essential nutrient 
in the construction of coronal spike-protein. 

L-histadine in numerous models also has been shown to be another 
excellent binder and mobilizer of zinc. Various enzymes that s
utilize zinc in the active center have histadine residues 
which hold the zinc in catalytic position. Zinc bis histadinate 
may therefore be an excellent choice to deliver zinc to corona 
virus infected cells. Histidine is not especially nutritious 
for coronal spike-proteins. 

L-carnosine may be the most idealic ionophore yet discovered 
for zinc influx into corona infected cells. Zinc carnosinate 
(also known as polaprezinc) is well absorbed orally and can even 
cross the blood-brain barrier. It has already proven useful to 
treat an ever increasing variety of illnesses. It also has 
antioxidant effects, which should be helpful in the more advanced 
cases of severe acute respiratory distress syndrome. 

Pyrithione with zinc has been used for many years as an antifungal 
agent for topical use only. It is an efficient ionophore for zinc. 
Zinc bis pyrithionate (ZnPyr2 )has already been shown to powerfully 
disable RdRp in vitro. However, little is known about its systemic 
toxicity. Therefore it cannot yet be safely recommended for internal 
use, unless or until this has been found to be safe. 

Ascorbic acid is often traditionally given with zinc as an antiviral 
strategy. Both items are worthy of considerable respect as immune 
supportive nutrients. Even though ascorbate binds well to zinc and 
chelates it, surprisingly no benefit for absorption nor influx 
occurs. Therefore ascorbate cannot be useful nor relied on as an 
ionophore for Zn++ influx. However, it remains an important nutrient 
for immune functions and serves as a soothing antioxidant in cases 
of severe acute respiratory distress syndrome, in which the 
tissues are overwhelmingly being damaged by reactive oxygen species. 

			Permeability Enhancers 
While not chelators of Zn++, and therefore not ionophores, there 
also exist small molecules that operate on cell membranes to make 
them more permeable. DMSO (dimethylsulfoxide) famously does this. 
So does the closely related molecule MSM (methyl sulfonyl methane, 
sometimes called DMSO2). Urea and others possess this capability. 
Once a suitable Zn++ ionophore has been selected for treatment, 
the combination zinc-ionophore product should penetrate even more 
efficiently, if a permeability enhancer is also administered. 

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