Glycosaminoglycan Interacting Small Molecule GISMO as Parkinson s Therapeutic

Glycosaminoglycan Interacting Small Molecule GISMO As Parkinsonandapos s Therapeutics ABSTRACT Current approved drugs for Parkinsonandapos s Disease PD treat the symptoms of the disease but do not stop disease progression This project is focused on developing a new disease modifying PD therapeutic with a novel mode of action that is expected to block disease progression Recent data indicate that heparan sulfate glycosaminoglycans HS GAGs are the receptors responsible for internalization and spreading of alpha synuclein proteopathic seeds across the CNS We propose that the inhibition of the HS GAG mediated internalization can be achieved by interfering with the interaction between alpha synuclein and HS GAGs and that targeting this interaction will lead to the identification of new treatments for PD and other synucleinopathies We have previously shown that Glycosaminoglycan Interacting Small Molecule GISMO are a new structurally diverse class of compounds that are biologically active in vitro and in vivo and we aim to target the HS GAG mediated internalization and aggregation of alpha synuclein proteopathic seeds with GISMOs In preliminary work for this project we screened a library of GISMO like compounds using a new alpha synuclein HS GAG interaction assay on well plates and identified hit compounds with inhibitory activity andgt that have been selected for further development In the proposed project we will first screen the hit compounds for inhibition of alpha synuclein internalization in neuronal cells and cytotoxic effects GISMO compounds are expected to inhibit HS GAG mediated alpha synuclein uptake Lead series of compounds with acceptable efficacy selectivity and safety in vitro will be then subjected to chemical optimization via medicinal chemistry The selected lead compounds will be evaluated by pharmacokinetics for oral bioavailability and brain penetrant properties Three chosen lead compounds will be subsequently tested in an animal model of Parkinsonandapos s Disease in collaboration with team of Dr Patrik Brundin Van Andel Research Institute Grand Rapids MI The successful completion of these studies will enable identifying a Preclinical Candidate for IND enabling studies The development of a disease modifying therapeutic would be the most significant advancement in Parkinson s disease therapeutics since the development of levodopa in the s The goal of this program is to develop a new drug for Parkinson s disease The available treatments for this disease reduce symptoms of motor impairment but do not prevent further neurodegeneration cell death from occurring This project is an investigation of small molecules that selectively prevent interactions between the disease associated protein alpha synuclein and cell surface heparan sulfate glycosaminoglycans aimed at preventing further neuronal damage in Parkinson s disease patients