PdCure.org

  Providing resources and ideas for therapies and medical developments for Parkinson's disease:

 

Project To Develop A New Mercury Chelator:

Goal:

Motivate the development of a new mercury chelator (because current offerings do more harm than good), for the purpose of mercury detoxification. With current mercury chelator options falling short, there is a compelling opportunity for pioneering chemists and research teams to lead an effort to develop a safer and more effective mercury detoxification process. Help shape a healthier world while unlocking immense potential for societal impact by championing this mission.

Patients:

All humans are exposed to some level of mercury intoxication. The environment of planet Earth has become irreversibly polluted with the neurotoxin, mercury. The burning of coal releases ethyl-mercury into the atmosphere which distributes it worldwide. Mercury has entered the ecosystem of the oceans, poisoning fish which gets consumed by humans. Products such as Compact Fluorescent Light Bulbs (CFLs) when broken release mercury as do thermometers and thermostats which may employ mercury. The extraction of gold in "artisanal" small scale mines use and release an estimated 2000 tons of mercury into the environment annually (ref UN). The widespread use of silver-mercury amalgam dental fillings (estimated 91,000,000 in US in 2018 survey) has put a mercury leaching time-bomb into the mouths of many. Some recently published papers address the link between mercury intoxication and alpha-synuclein fibrillation and Parkinson's disease (reference: Mercury and Parkinson's Disease: Promising Leads, but Research Is Needed (Torrey and Simmons, 2023).

It is almost impossible to avoid mercury intoxication. Those coastal communities which rely on fish for food, those with dental amalgams or those exposed from any other factor are at risk of the neurological effects of mercury toxicity.

 

Mercury element symbol

Hg is derived from the Latin name for mercury: hydrargyrum

 

Problem:

Mercury Chelation Does Not Work:

Current chelator compounds are either ineffective at removing mercury from the body or they are ineffective at maintaining a bond with mercury resulting in the release of mercury allowing it to relocate to sensitive areas of the body such as the brain. A study by H. V. Aposhtian et al., found that current chelators (DMPS, DMSA, glutathione (GSH) and lipoic acid), alone or in combination, do not decrease the brain burden of mercury.

References:

Mercury Release and Relocation:

A study by the renowned researcher, Graham George showed that current chelators such as DMPS or DMSA do not maintain a bond with mercury and do not bond in a fashion expected by chemists. DMPS and DMSA stir up mercury, where it then travels to high mercury affinity areas like the brain. Many of the chelators in use today were developed in the 1940's and 1950's and are innefective or outright dangerous.

Mercury chelation does not work!

References:

Mercury Eviction:

Once the chelator has bonded with mercury, it has to be recognized by the kidneys or liver so that it may be evicted from the body as urine or as stool respectively. Not all chelators are effective at evicting mercury. This is true for the chelator NBMI which has been shown to fail at this task.

References:

The Brain Attracts Mercury:

The substance responsible for pigmentation of the skin is known to be melanin. More melanin results in darker skin. Highly pigmented neurons of the brain like the substantia nigra are also given their color from the presence of melanin, more specifically, neuromelanin. Studies have shown that elemental analyses of neuromelanin revealed a high sulfur content. Sulfur in turn has a high affinity for mercury. It is this sulfur affinity that most chelators rely upon to bond with mercury. This affinity also draws mercury to the neurons of the substantia nigra. A chelator should form a bond with mercury which is stronger than that of neuromelanin.

Reference:
  • Substantia nigra neuromelanin: structure, synthesis, and molecular behaviour (2001)
    "... neuromelanin is indeed a genuine melanin because it has a stable free radical structure and avidly chelates metals."
    "Elemental analyses of neuromelanin revealed a high sulphur content ..."
    "Neuromelanin from the substantia nigra can interact with many heavy metal ions such as zinc, copper, manganese, chromium, cobalt, mercury, lead, and cadmium; in addition, it binds iron particularly strongly."

For more discussion on mercury, chelation and Parkinson's see Mercury and Parkinson's Disease.

 

NBMI Hg chelate

NBMI: this chelator bonds to the mercury atom (180 deg) but fails to be evicted from the human body

 

NBMI Hg chelate

DMSA: this chelator does not typically bond in this geometric structure due to mercury's propensity for a 180 deg bond.

 

NBMI Hg 2x2 configuration

DMSA: Research by Graham George shows that the typical DMSA chelate structure with Hg is 2 DMSA bonding with 2 Hg. This chelator gets evicted from the body, primarily by the kidneys, but makes a structurally weak bond to the mercury atom and generally drops it before being evicted

Requirements For A New Chelator:

  • Must be able to administer by IV, injection or orally.
  • Must have a high affinity for mercury: must be able to break the bond mercury has with tissue to prefer making a bond with the chelator.
  • Must be non-toxic, not carcinogenic, not harmful.
  • Must be able to form a chelate (the resulting compound of the chelator bonded with mercury) which the body can excrete via the kidneys or via the liver
  • Once bonded with mercury, the chelator must not drop this bond to release the mercury allowing redistribution
Advanced requirements (high expectations):
  • Must be able to pass through the blood-brain-barrier (BBB)
  • Must be able to have an affinity to mercury higher than that of brain tissue. Note that dark brain matter has higher levels of neuro-melanin which is high in sulfur. Sulfur is typically used in traditional chelators due to its affinity for mercury. May need multiple sulfur bonds or may need to employ selenium as the atom for bonding with mercury
  • Must be able to pass through cell walls to bond with and remove mercury wherever it is

 

Scroll of requirements: Creative Commons

 

Chelator Development Using Computational Chemistry Tools:

Many of the chelation compounds in use today were developed during the WW2 era or at the very least, prior to the availability of tools such as "Computational Chemistry". These tools allow for the simulation of chemical reactions, compound optimization, compound discovery, virtual screening (VS) and high throughput screening (HTS). They are ideally suited for the discovery, simulation and optimization of potential chelators including the optimization and rework of current chelators. One key CADD feature is "docking" or the modeling of binding energy to a target where the bond of the chelator to mercury can be simulated. The virtual world allows for rapid development and experimentation.

Computer-Aided Drug Design (CADD) software:

Compounds developed can be shared digitally in any of the following public databases:
  • PubChem - chemical information
    One can also download current chelator compound digital models (DMSA, DMPS, NBMI, ALA, MiaDMSA, Glutathione, etc)
  • BindingDB - molecules with drug-like properties and their binding affinities
See table 6: Software and resources for computational medicinal chemistry (2012)

 

Alpha-synuclein protein 6PEO

 

Chelator Creation:

While the virtual world of computational chemistry allows for rapid prototyping, at some point the chelator compound must be created in order to be tested or applied. There are many university and commercial labs that can perform this task.

 

laboratory

 

Chelator Validation:

A true validation to test if the chelator is not redistributing mercury to the brain, can only be performed on mice as an autopsy is required to measure the brain burden of mercury for both the mice testing the chelator and for the control specimens.

The following paper is a good example of chelator validation using mice: Vitamin C, Glutathione, or Lipoic Acid Did Not Decrease Brain or Kidney Mercury in Rats Exposed to Mercury Vapor (Aposhian et al., 2003)
This paper covers the mercury intoxication of mice, the measurement of the effects of chelation on the mouse brain and the effects of mercury mobilization. The paper also covers compliance with animal treatment as well as the use of control and sentinal specimines.

There are some chelators which have not been shown to be qualified as safe from redistributing mercury and need to be validated. There are also some which have been improperly validated. Proof that a chelator is non-toxic, lowers the blood level of mercury or improves organ toxicity, is not a validation that the chelator does not increase the brain burden of mercury.

Chelators not tested or not adequately tested:
  • miaDMSA
  • Chlorella
  • Selenium supplements
  • Cysteamine

 

lab mice

 

Clinical Trials:

A new chelator could be used under "compassionate use" also known as "expanded access programs" (EAPs), "right to try", as a supplement which makes no claims, or get FDA phase 1, 2 and 3 approval.

FDA Compassionate Use:

This protocol relates to the use of an investigational medicine outside of a clinical trial to treat a serious or life-threatening condition. Mercury toxicity is often such a condition. A request for "Compassionate Use" or "Expanded Access" must be requested by a licensed doctor and approved by the FDA for an individual. Requests are made by phone or email. Adverse events must be immediately reported to the FDA.

EAPs conditions of use:
  • has a serious and life-threatening condition
  • has no other comparable treatment option
  • has exhausted approved treatment options
  • likely to have benefits that outweigh the risks
  • if drug is in clinical trials but does not qualify

See FDA expanded access contact information and forms.

Right To Try:

A US law passed in 2018 provides another way to access unapproved drugs. Right to try is only for drugs in a FDA phase 1 trial. This law is used to request access to an unapproved drug from a company that makes it, without having to go through the FDA.

FDA Phase 1, 2, 3 Trials:

Consultants and contractors:

 

Drug treatment Creative Commons

 

Potential Sources of Funding:

We have a chicken and egg problem. Those financing an endeavor want to see a research team who will develop the chelator. It's hard to put together a scientific team when we can't identify financing.

Potential Funding Sources:

 

money image attribution: Pix4free.org

 

Call To Action:

This web page is meant to instigate and inspire a call to action to take a journey towards pioneering the development of a new mercury chelator. The demand it urgent. It is hoped that development teams can be formed to harness the power of modern computational chemistry tools to engineer a breakthrough solution for a safe and effective mercury chelation compound. This call to action is dependent upon the expertise and passion of dedicated scientists and research teams to bring this vision to life. Join us to unite and rally passionate scientists and experts to collaborate on the quest to safeguard global health and environmental well-being from the harmful effects of mercury.

Note that this website does not have the financial or technical means to undertake this call to action.

 

Creative Commons - runners

 

 

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