Targeted treatment of oxidative stress via peroxide-activated prodrug

A new peroxide-activated prodrug that releases an active drug only where it is needed can treat neuropathic and arthritic pain. The prodrug both shows potential as a treatment for human oxidative stress disorders and exemplifies the 1,2-dicarbonyl platform technology for peroxide-activated prodrugs.
Targeted treatment of oxidative stress via peroxide-activated prodrug
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The pinnacle of drug development is to engage with the biological target only when and where it is required in the body, whilst not engaging with off-targets and other parts of the body. The result of this are highly efficacious drugs with excellent safety and side effect profiles.

Our research team from the University of Adelaide, University of Texas MD Anderson Cancer Center and Texas Southern University came together to develop a tissue targeted treatment for neuropathic pain, now published in Nature Biotechnology. The approach we have developed could also be applied to other diseases of oxidative stress and demonstrates the potential of the tissue-targeting chemical technology as a candidate drug class with applicability to an even broader range of oxidative stress disorders. Ultimately, we have demonstrated this technology could be utilized to create numerous other drugs with highly specific release of a drug at a disease site, treating a disease and eliminating possible side-effects.

How can a drug be targeted to sites of oxidative stress?

Oxidative stress is characterized by an imbalance between the amount of reactive oxygen species (ROS) produced versus the capacity of cells or tissues to get rid of ROS or repair the damaged the increased ROS has caused. The biological peroxides hydrogen peroxide and peroxynitrite are examples of relatively long-lived ROS and are overproduced at sites of oxidative stress.

We thought to utilize these biological peroxides as molecular triggers for a prodrug that is activated only at sites of oxidative stress. This thought led us to the Baeyer-Villiger oxidation, a reaction which requires an oxidant, such as the biological peroxides, to perform a chemical transformation. Baeyer-Villiger oxidation is a well-known chemical reaction, first reported in 1899 and used widely in synthetic organic chemistry usually to convert ketones into esters. However, we thought to take the reaction into biology by employing the more reactive 1,2-dicarbonyl moiety for biological peroxide prodrug activation. The 1,2-dicarbonyl moiety reacts with biological peroxides to produce a transient anhydride which immediately hydrolyzes in water to release a carboxylic acid alongside other byproducts, such as carbon dioxide. This allows drugs containing a carboxylic acid to be modified to 1,2-dicarbonyl prodrugs, thus acquiring the ability to release the active drug at sites of oxidative stress. Since the activity of a drug is highly sensitive to changes to the chemical structure, the 1,2-dicarbonyl prodrug can be designed so that it is inactive until it reaches a site of oxidative stress and undergoes activation by reacting with biological peroxides.

How did we design our targeted prodrug?

We chose to modify the FDA-approved drug monomethyl fumarate (MMF) with the 1,2-dicarbonyl moiety to create our peroxide-activated MMF prodrug. MMF was chosen since it contains a carboxylic acid, therefore making it a viable product of the reaction between a 1,2-dicarbonyl and biological peroxides; additionally, MMF is an activator of the antioxidant Nrf2 pathway and can reverse the localized oxidative stress. We initially proposed three 1,2-dicarbonyl prodrugs of MMF and found that the alpha-ketoester analogue (named 1c in our paper) gave rapid peroxide-responsive release of MMF in chemical and in vitro studies.

Tissue targeted drug release reverses chronic pain in mice

We tested the ability of our peroxide-activated 1,2-dicarbonyl prodrug of MMF in a mouse model of peripheral nerve injury, where nerves running to the hind paw of one side of the mouse are surgically injured. This results in measurable pain behaviours in the animals and oxidative stress at the nerve injury site and up to where the nerve meets the spine, with the nerve on the other side of the spine remaining unaffected. We found that our prodrug reversed pain behaviours against multiple types of stimuli, with Nrf2 pathway activation (our desired biological target) only observed at the nerve where the injury occurred and not on the nerves on the other side, nor in other tissues such as the heart, liver, kidney and lung. Additionally, our prodrug does not induce tolerance (a major limitation of powerful painkillers such as morphine), demonstrated by maintained pain relief upon repeated dosing. Pain relief was also provided by our prodrug in other mouse models of pain that feature oxidative stress such as osteoarthritis, chemotherapy-induced peripheral neuropathy and diabetic neuropathy.

In humans, MMF causes side effects such as immunosuppression and skin flushing, which we aimed to reduce using our targeted drug delivery. Our prodrug demonstrated that levels of glutathione (a highly important biological molecule) in the mice were not reduced, and skin temperature did not increase, which are effects seen when the mice are given MMF.
Overall, our 1,2-dicarbonyl prodrug of MMF that reacts with biological peroxides present in high amounts at sites of oxidative stress can relieve pain via targeted activation of the Nrf2 pathway and suppress the systemic action of MMF to reduce the related side effects.

What is next for the peroxide-activated MMF prodrug?

Our prodrug has been successfully administered in a range of animal models of chronic pain. With the success of the targeted release of MMF to treat some examples of diseases of oxidative stress, the applicability of the prodrug to oxidative stress diseases besides pain should be established. The pharmacology behind the prodrug now also needs to be comprehensively understood, especially monitoring all metabolites of the prodrugs across different tissues. Further efficacy and safety testing is currently underway and is required before human clinical trials can be conducted. We have also recently established a company based in the USA and Australia to commercialize our findings.

The future of 1,2-dicarbonyl compounds as targeted prodrugs

We expect that other drugs can be chemically modified with a 1,2-dicarbonyl moiety to confer tissue-specific activation of a drug at a site of oxidative stress. This tissue-specific activation may result in improved side effect profiles and efficacy, potentially allowing the use of drugs in diseases where their use is currently limited due to poor risk-to-benefit ratios. The potential of 1,2-dicarbonyl prodrugs demands thorough investigation into the fundamental chemistry and application in diseases according to their pathologies, breaking open a field of science focused on the development of pathology activated prodrugs.

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Medicinal Chemistry
Physical Sciences > Chemistry > Organic Chemistry > Medicinal Chemistry
Neuropathic pain
Life Sciences > Health Sciences > Clinical Medicine > Neurology > Neurological Disorders > Neuropathic pain
Small Molecules
Life Sciences > Health Sciences > Biomedical Research > Pharmacology > Small Molecules
Osteoarthritis
Life Sciences > Health Sciences > Clinical Medicine > Diseases > Rheumatic Diseases > Osteoarthritis
Neuroimmunology
Life Sciences > Biological Sciences > Neuroscience > Neuroimmunology