Research

Development of Tau-aggregation Inhibitors

Tau protein has been largely regarded as a promising target for AD because paired helical filaments (PHFs) and neurofibrillary tangles (NFTs) that are mainly composed of various tau species have been typically observed in brains of AD patients. Moreover, the severity of tau pathology is closely correlated with the progression of cognitive decline of AD patients. Abnormal phosphorylation of tau followed by dissociation from microtubules has been considered as the key event initiating tau pathologies in AD and other tau-related diseases (tauopathies). Dissociation of hyperphosphorylated tau from microtubules produces greater amount of cytosolic tau that is prone to self-aggregation. Recently, it is increasingly admitted that tau oligomers might be the most toxic tau species resulting in neurotoxicity and neurodegeneration in AD. Hence, inhibition of the process to produce toxic tau oligomers has been considered an effective therapeutic approach for AD. In this respect, we are actively developing tau-aggregation inhibitors.

Development of Biased-S1P1 Agonists

Fingolimod is a first-approved oral medication for the treatment of multiple sclerosis targeting Sphingosine-1-phosphate receptor 1 (S1P1). S1P1 is a G-protein coupled receptor (GPCR), and upon binding of Fingolimod to S1P1, G-protein-mediated- and β-arrestin-mediated signaling pathways are simultaneously activated. Later, desensitization and internalization of S1P1 is induced by β-arrestin by which Fingolimod exerts its therapeutic effects. However, concurrent stimulation of G-protein-mediated signaling also leads to activation of the GIRK channels which may be responsible for bradycardia and/or atrioventricular block, serious side effects triggered by administration of Fingolimod. Therefore, biased S1P1 agonists that can selectively stimulate β-arrestin-mediated signaling pathways are considered as next-generation medications that can maximize therapeutic windows minimizing adverse effects.

Fragment Screening

Fragment screening is a kind of different screening strategy as compared to high-throughput screening and is for the identification of fragments that show binding affinities to targets of interest. A fragment means a compound of which molecular weight ranges approximately between 100 and 200. After finding several hit fragments, we increase and optimize potency of those by growing sizes of fragments, linking hit fragments, and merging hit fragments with the help of structural biology. In this way, we can create a number of novel compounds through alteration of identity and orientation of fragments. As a result, we can obtain biological active compounds possessing novel physicochemical properties and patentability. One challenge is that the binding affinity of a fragment to a certain target is inevitably not strong. Therefore, in order to detect the weak molecular interactions, we collaborate with the KIST NMR team and utilize 800 MHz NMR at KIST.

REFs: 1. J. Chem. Educ. 2011, 88, 990–994. 2. https://komal-gh-work.colibriwp.com/pharmaherald/medical/fragment-based-drug-discovery-market-in-global-industry-share-trends-insight-and-application-2019-2026/