Inhibiting Microbial Metabolism of Levodopa to Increase Availability in the CNS

Parkinson’s disease (PD) impacts 10 million people globally, with 60,000 Americans newly diagnosed every year. Levodopa remains the gold standard treatment for PD, despite limitations including side effects and peripheral metabolism. Current research has focused on improving dosing formulations of levodopa, as well as newer antibody-based therapeutics in clinical trials. Despite the advances in levodopa dosing, peripheral metabolism of the drug before it reaches the CNS remains a major challenge. Levodopa is commonly dosed in combination with another drug, carbidopa, which serves to inhibit levodopa degradation in the mammalian gut via decarboxylation to dopamine within the GI tract. However, even with combination therapy, up to half of the dosed levodopa is not available in the CNS, impacted mainly by the gut microbiome. Side effects of levodopa treatments, such as dyskinesia, nausea, and diarrhea, are related to changing plasma concentrations of the drug and increased dopamine in the GI tract.

Technology: The Balskus Lab has discovered the bacterial enzyme responsible for levodopa decarboxylation and a small molecule inhibitor of peripheral levodopa metabolism by gut bacteria. (S)-α-fluoromethyltyrosine (AFMT) is a covalent inhibitor that is highly specific for bacterial decarboxylases, compared to carbidopa which targets the human decarboxylase and does not significantly inhibit the bacterial enzyme. AFMT does not inhibit the growth of levodopa-metabolizing microbes and is non-toxic to mammalian cells. Co-administering levodopa, carbidopa, and AFMT has led to increased circulating levodopa levels in a mouse model.

Advantages: AFMT leads to increased bioavailability of levodopa and, by minimizing off-target metabolism, has the potential to generate more consistent and reproducible levodopa dosing between patients. Decreasing peripheral dopamine may also limit GI side effects of levodopa treatment.

Intellectual Property Status: Patent(s) Pending