L-dopa is metabolized into dopamine in the dopaminergic neurons by L-aromatic amino acid decarboxylase. However, only 1-5% of L-dopa enters the dopaminergic neurons. The remaining L-DOPA is often metabolized to dopamine elsewhere. Due to feedback inhibition, L-dopa results in a reduction in the endogenous formation of L-dopa, and so it becomes less effective over time.

PD most visibly effects the substantia nigra region of the brain which houses dopamine producing neurons. Dopamine is a neurotransmitter that among other things regulates movement and balance. Examination of PD patient's brains have shown the presence of protein aggregates similar to those present in Huntington's Disease (HD) and Alzheimer's Disease (AD).  In PD, Lewy bodies are primarily composed of the protein alpha-synuclein.  As in other degenerative diseases, the role of these aggregates in PD progression are not well understood.

Zenobia Therapeutics is seeking a neuroprotective treatment that would significantly decrease the degeneration of neurons impacted by PD. A target for such a treatment has been identified through the examination of PD patients. Specifically, at least 6 disease causative mutations have been observed within the gene encoding the protein, leucine-rich repeat kinase-2 (LRRK2).  This gene is expressed at high levels in dopamine producing neurons and mutation appear to be associated with both sporadic onset and hereditary PD. Zenobia is working with the most common mutation, G2019S which has been shown to activate LRRK2 and to result in neuronal death.

LRRK2 encodes a multi-domain protein that includes an ankryin repeat region, a leucine-rich repeat (LRR) domain, a Roc-Cor ras-like GTPase domain, a protein kinase domain and a WD-40 domain. G2019S is located on the protein kinase domain at the highly conserved DF(Y)G motif (DYG to DYS). DFG is located at the active site of protein kinases, and is associated with conformational changes from active to inactive conformation.  Zenobia is currently funded by the Michael J Fox foundation to determine the three dimensional X-ray structure of wild-type and G2019S LRRK2 to better understand the mechanism of activation of kinase activity.  This crystal structure will also be used to conduct and analyze results from an experimental fragment screen and in analysis of results from Zenobia's ongoing computational screens and structure-directed lead optimization.

In addition to Zenobia's efforts to determine the X-ray crystal structure of LRRK2, computational fragment screens have been conducted to identify starting points for fragment-to-lead optimization. Using our proprietary computational software we have identified highly ligand efficient starting points with parameters consistent with blood-brain barrier (BBB) penetration including low polar surface area, number of hydrogen bonds and molecular weight. Our software is currently being used to optimize these compounds into lead compounds appropriate for optimization into clinical development candidates. Our current leads are showing neuroprotective effects in cells in the laboratory of Dr. Christopher Ross, Johns Hopkins University.