पार्किंसंस रोग के उपचार में निर्णायक अनुसंधान
A molecule that can cure Parkinson's disease: Technology Transfer Agreement Between University of Delhi, McLean Hospital and NurrOn Pharmaceuticals, Boston, USA
Parkinson's disease (PD) is a neuro-degenerative disorder that affects the motor system in the humans and estimated 10 million people worldwide have PD. The common symptoms of PD are tremor, rigidity, slowness of movement, and difficulty with walking. It also causes cognitive and behavioural problems such as depression, anxiety, and apathy. The motor symptoms of PD result from the death of neuron cells in the substantia nigra, which is located in the midbrain, and it causes deficiency of dopamine.
There is no drug available for the treatment of PD; the available treatments aim to reduce the PD symptoms, for which L-DOPA is commonly used, and which are not very effective as the disease progresses.
The aim of drug development for the treatment of PD is to activate the protein transcription factors that are essential for the survival of Dopamine neurons. There are two pathways for the dopamine neurons and both of these pathways merge on the common nuclear receptor protein called Nurr1. So, one can consider Nurr1 as a potential target for the development of drug candidates for the treatment of PD. Nurr1 maintains the dopamine neurons and also protects the neurons from inflammation in case of PD and other neurodegenerative diseases. But for a long time, Nurr1 was considered to be an orphan receptor that does not have classic ligand binding pocket. The binding pocket of Nurr1 is occupied by bulky, hydrophobic amino acid side-chains which restrict the entry/interaction of a ligand. Prof Kim and others experimentally demonstrated that Nurr1 is crucial for the health of dopaminergic neurons and any decrease in the Nurr 1 activity causes the death of these neurons and that leads to PD.
So the goal of the research was to identify an active ligand that can activate the so-called ‘orphan’ Nurr1 protein. Snyder et al in 1987 experimentally proved that chloroquine can retard the progression of PD and published their work in the esteemed Nature journal, but there was no follow-up. Prof Kim at McLean Hospital, with an aim to identify a Nurr1 agonist, screened 960 FDA approved drugs using a developed high-throughput assay system and found three hits (chloroquine, amodiaquine and glafenine) that had a common 4-aminoquinoline pharmacophore. Concurrently, the research group led by Prof DS Rawat at the University of Delhi have been working on the development of aminoquinoline based hybrid molecules as potential drug candidates to be used against the malaria parasite. During this period, Prof DS Rawat started collaborating with Prof Kim and the project was funded by MJ Fox foundation in 2014. A formal MoU was signed between the University of Delhi and the McLean Hospital, Boston, USA which resulted in a joint US patent and PCT application. A massive synthetic program was initiated at University of Delhi and over 650 new compounds were synthesized and subsequently screened for their Nurr1 activation potential. 15 initial hits were identified and finally two compounds were selected for the drug development purposes (pre-clinical/clinical phase studies). These molecules, along with chloroquine and amodiaquine (which were identified in the initial screening) were experimentally demonstrated to bind and activate the Nurr1 and improve the PD related symptoms in a rat model to a great extent without any toxicity. University of Delhi and McLean Hospital have signed a technology transfer agreement with NurrOn Pharmaceuticals, Boston, USA for the development of these molecules as novel disease-modifying drugs for the treatment of Parkinson's disease.