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Design of Neuroprotective Drugs to Reduce Oxidative Damage and Alpha-synuclein Toxicity in Parkinson's Disease

Objective/Rationale:
Exposure to chemical toxins that stimulate the production of reactive oxygen and nitrogen species (RONS) causes neuronal degeneration and can lead to Parkinson’s disease (PD). Several molecules that protect against RONS damage have been tested in human trials, and although clinical benefit has been observed, the poor pharmaceutical properties of many of these compounds limit their efficacy. This project is to develop RONS interceptors with superior pharmaceutical properties for treating PD.

Project Description:
In this project we will improve the pharmaceutical properties of a potent RONS interceptor, CT-3, that is safe in humans and has shown clinical benefit for an unrelated disease. At high doses, CT-3 is effective in experimental models of PD. We have developed a unique strategy to modify CT-3 to make it a better drug for treating human PD. The project involves synthesis of novel variants of CT-3 and profiling them in biochemical and cell-based assays. Compounds with properties superior to CT-3 will be studied in animals to determine their pharmaceutical properties and brain penetration. The best compounds will be tested for efficacy in the alpha-synuclein rodent model, which exhibits many of the hallmarks of human PD. Positive results will support moving compounds into human trials.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Substantial evidence implicates RONS as toxic to dopaminergic neurons, and RONS damage is prevalent in brain lesions of PD patients. Intercepting RONS would be a disease modifying therapy that could halt disease progression. The drug is expected to be taken daily, and over time may allow for recovery of neurological function. If safety permits, preventive treatment could be considered for high-risk groups.


Anticipated Outcome:
This project will determine whether chemical modification can improve the drug-properties of CT-3. If successful this could lead to a new drug candidate for PD and provide further insights into the role of RONS in human PD. Moreover, several studies show a compelling link between RONS pathologies and alpha-synuclein, which is mutated in familial PD. This project will determine whether intercepting RONS can protect against alpha-synuclein mediated toxicity and neuronal degeneration.


Researchers

  • Stig K. Hansen, PhD

    San Francisco, CA United States


  • Daniel A. Erlanson, PhD

    San Francisco, CA United States


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