Category: Parkinson's Disease (Other)
Objective: We developed a new small molecule drug candidate that would increase the effectiveness of dopamine delivery to the brain. We also sought to mitigate alpha-synuclein misfolding concurrently with dopamine therapy, providing dual drug mechanisms to replace dopamine and reduce misfolding of alpha-synuclein.
Background: Levodopa/carbidopa therapies can partially abate motor symptoms associated with PD, with no current treatment existing to reduce or eliminate alpha-synuclein misfolding. There is currently an unmet medical need to concurrently prevent misfolding of alpha-synuclein and optimize the bioavailability and effective absorption of dopamine.
Method: We developed a novel molecule (Dubbed Pegasus) that combines dopamine via a molecular linker to non-antibiotic tetracycline. Animal models of PD, including A53T (human alpha-synuclein) and MPTP mice were treated with 50mg/kg Pegasus versus clinical doses of levodopa and assessed via behavioral, biochemical and histopathological assays. We performed complete pre-IND studies, including drug formulation, PK and bioanalysis, pharmacological screening of potential off-targets, ADMET and DMPK studies.
Results: Pegasus was formulated as an oral drug to optimize stability, absorption and bioavailability. Pegasus is a pro-drug that releases intact dopamine and tetracycline via dissolution of the linker. Both dopamine and tetracycline are detected in the brain and appear to match plasma (1:1) concentration. Treatment with pegasus significantly lowered the level of alpha-synuclein in A53T mice, increased dopamine concentration in the brain and reversed motor deficits in disease models. The efficacy and biomarker studies were supported by PK that showed signficant improvement of half-time (>12 hours) and bioavailability compared to excisting levodopa formulations. Pegasus displays highly acceptable metabolic and pharmacological profile with no significant drug-drug interaction and an adequate therapeutic index. We conducted pre-IND, ADMET and DMPK studies according to FDA guidelines.
Conclusion: Our results show highly desirable efficacy via dual brain dopamine replacement as well as mitigation of alpha-synuclein misfolding. Our IND-enabling studies support safety evaluations to progress to First-in-Human (FIH) and SAD/MAD studies.
To cite this abstract in AMA style:
C. Moussa. A novel pro-drug overcomes short-half life and absorption challenges and increase brain penetration of dopamine as a potential therapy for Parkinson’s disease [abstract]. Mov Disord. 2026; 41 (suppl 1). https://www.mdsabstracts.org/abstract/a-novel-pro-drug-overcomes-short-half-life-and-absorption-challenges-and-increase-brain-penetration-of-dopamine-as-a-potential-therapy-for-parkinsons-disease/. Accessed October 1, 2026.« Back to 2026 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/a-novel-pro-drug-overcomes-short-half-life-and-absorption-challenges-and-increase-brain-penetration-of-dopamine-as-a-potential-therapy-for-parkinsons-disease/