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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 pubmed.gov 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-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
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.
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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