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Simple Molecular Reagents to Treat Alzheimer’s Disease
- Researchers report minimalistic principles for designing small molecules with multiple reactivities against dementia. -
Sometimes the most complex problems actually have very simple solutions. A group of South Korean researchers reported an efficient and effective redox-based strategy for incorporating multiple functions into simple molecular reagents against neurodegenerative disorders. The team developed redox-active aromatic molecular reagents with a simple structural composition that can simultaneously target and modulate various pathogenic factors in complex neurodegenerative disorders such as Alzheimer’s disease.
Alzheimer’s disease is one of the most prevalent neurodegenerative disorders, affecting one in ten people over the age of 65. Early-onset dementia also increasingly affects younger people.
A number of pathogenic elements such as reactive oxygen species, amyloid-beta, and metal ions have been suggested as potential causes of Alzheimer’s disease. Each element itself can lead to Alzheimer’s disease, but interactions between them may also aggravate the patient’s condition or interfere with the appropriate clinical care.
For example, when interacting with amyloid-beta, metal ions foster the aggregation and accumulation of amyloid-beta peptides that can induce oxidative stress and toxicity in the brain and lead to neurodegeneration.
Because these pathogenic factors of Alzheimer’s disease are intertwined, developing therapeutic agents that are capable of simultaneously regulating metal ion dyshomeostasis, amyloid-beta agglutination, and oxidative stress responses remains a key to halting the progression of the disease.
A research team led by Professor Mi Hee Lim from the Department of Chemistry at KAIST demonstrated the feasibility of structure-mechanism-based molecular design for controlling a molecule’s chemical reactivity toward the various pathological factors of Alzheimer’s disease by tuning the redox properties of the molecule.
This study, featured as the ‘ACS Editors’ Choice’ in the May 6th issue of the Journal of the American Chemical Society (JACS), was conducted in conjunction with KAIST Professor Mu-Hyun Baik’s group and Professor Joo-Young Lee’s group at the Asan Medical Center.
Professor Lim and her collaborators rationally designed and generated 10 compact aromatic molecules presenting a range of redox potentials by adjusting the electronic distribution of the phenyl, phenylene, or pyridyl moiety to impart redox-dependent reactivities against the multiple pathogenic factors in Alzheimer’s disease.
During the team’s biochemical and biophysical studies, these designed molecular reagents displayed redox-dependent reactivities against numerous desirable targets that are associated with Alzheimer’s disease such as free radicals, metal-free amyloid-beta, and metal-bound amyloid-beta.
Further mechanistic results revealed that the redox properties of these designed molecular reagents were essential for their function. The team demonstrated that these reagents engaged in oxidative reactions with metal-free and metal-bound amyloid-beta and led to chemical modifications. The products of such oxidative transformations were observed to form covalent adducts with amyloid-beta and alter its aggregation.
Moreover, the administration of the most promising candidate molecule significantly attenuated the amyloid pathology in the brains of Alzheimer’s disease transgenic mice and improved their cognitive defects.
Professor Lim said, “This strategy is straightforward, time-saving, and cost-effective, and its effect is significant. We are excited to help enable the advancement of new therapeutic agents for neurodegenerative disorders, which can improve the lives of so many patients.”
This work was supported by the National Research Foundation (NRF) of Korea, the Institute for Basic Science (IBS), and the Asan Institute for Life Sciences.
Image credit: Professor Mi Hee Lim, KAIST
Image usage restrictions: News organizations may use or redistribute this image, with proper attribution, as part of the news coverage of this paper only.
Publication:
Kim, M. et al. (2020) ‘Minimalistic Principles for Designing Small Molecules with Multiple Reactivities against Pathological Factors in Dementia.’ Journal of the American Chemical Society (JACS), Volume 142, Issue 18, pp.8183-8193. Available online at https://doi.org/10.1021/jacs.9b13100
Profile:
Mi Hee Lim
Professor
miheelim@kaist.ac.kr
http://sites.google.com/site/miheelimlab
Lim Laboratory
Department of Chemistry
KAIST
Profile:
Mu-Hyun Baik
Professor
mbaik2805@kaist.ac.kr
https://baik-laboratory.com/
Baik Laboratory
Department of Chemistry
KAIST
Profile:
Joo-Yong Lee
Professor
jlee@amc.seoul.kr
Asan Institute for Life Sciences
Asan Medical Center
(END)
2020.05.11 View 22904 -
Six Organizations Join Forces to Induce Projected National Brain Institute to Daejeon
Six major organizations including KAIST have joined forces to help Daejeon City to win the government approval to build the envisioned Korean Brain Institute in Daedeok Research Complex.
The six organizations signed a memorandum of understanding on cooperating in establishing the government-funded institute built within the Daedeok Research Complex in the city of Daejeon, at KAIST on Jan. 14. The six organizations are KAIST, the Daejeon City Government, Korea Research Institute of Bioscience and Biotechnology, Korea Research Institute of Standard and Science, Asan Medical Center, and SK Corp., a pioneer in effective therapeutic invention for serious brain disorders.
The partnership of the six organizations is expected to bring a broad-based cooperation opportunities and create a massive synergy effect in the brain science researches and the development of new therapeutic treatment for brain disorders by combining their resources and infrastructures.
The six organizations have also built an international research network with such globally-renowned brain research institutions as RIKEN, a large natural sciences research institute in Japan, Max Plank Institute in Germany, Federal Institute of Technology, Lausanne, in Switzerland and Brain Research Institute of University of Queensland in Australia. The research network is under the support and guidance of Dennis Choi, a prominent neuroscientist who once served as the President of the Society for Neuroscience and is currently a professor in the Departments of Neurology and biology at Emory University.
The tentatively titled Korea Brain Institute is envisioned to help fight brain disorders and create Korea"s new growth engine, as well as lengthening life span, by conducting convergence researches in nero science, brain science and pharmacology. If the consortium of the six organizations wins the government approval to build the proposed institute within the Daedeok complex, the central government and the Daejeon city government are expected to pour a total of 329.7 billion won into the project by 2020.
2009.01.14 View 25361