3. Research‎ > ‎

a. Projects

Project I. Design of Small Molecules as Chemical Reagents or Probes for Targeting and Modulating Metal–Misfolded Proteins in Human Neurodegenerative Diseases

A distinct feature of human neurodegenerative diseases is accumulation of misfolded proteins (e.g., for Alzheimer’s disease (AD), aggregates of amyloid-β (Aβ) or hyperphosphorylated  tau). Some in vitro and in vivo studies have suggested that the interactions between metal ions and misfolded proteins could be associated with disease development. This relationship between metal-associated misfolded proteins (metal-misfolded proteins) and neuropathogenesis has not been clearly revealed, however. To gain a greater understanding of this relation, Lim lab has been focusing on designing small molecules as chemical reagents or probes that can target specifically metal-misfolded proteins, modulate their interactions, and eventually alter their reactivity (i.e., aggregation, ROS production). Lim lab has recently prepared and characterized several series of small molecules that are capable of targeting and modulating metal-Aβ complexes specifically, and subsequently diminishing metal-Aβ toxicity in vitro, in living cells, and in vivo (a transgenic mouse model of AD).

Projects II-IV. Development of Small Molecules or Metal Complexes as Potential Therapeutics Targeting Multiple Pathological Facets in Human Neurodegenerative Diseases

In human neurodegenerative disorders, multiple factors and processes have been suggested to be involved in neuropathogenesis. These pathological elements include enzymes (e.g., acetylcholinesterase (AChE) for Alzheimer’s disease, monoamine oxidase B (MAOB) for Parkinson’s disease) and reactive oxygen species (ROS), along with metals and misfolded proteins (described in Project I).

Project II: Lim lab has been developing small molecules as enzyme inhibitors to understand the role of these enzymes in disease development and contribute to drug discovery.

Project II: In order to discover effective therapeutics for devastating brain disorders (Alzheimer’s disease and Parkinson’s disease), Lim lab has been taking an innovative approach to designing a single molecule targeting and subsequently regulating multiple pathological factors [i.e., metals, misfolded proteins, ROS, and enzymes (AChE or MAOB)]. Due to complicated, interconnected pathogenesis in human neurodegenerative diseases, an effective drug for multiple targets would be desirable.

Project IV: In cellular antioxidant defense systems, catalase acts as an enzymatic scavenger of H2Oconverting it to dioxygen and water. To clarify the mechanism of H2O2 decomposition by catalase, which is believed to involve a high-valent metal-oxo intermediate, Lim lab has been investigating the reactivity of synthetic oxoiron species with H2O2. Based on these studies and inspired by the structure and function of catalase, Lim lab will construct efficient detoxifiers of H2O2 in biological systems.