A substance that worsens dementia has become a "switch" that initiates treatment. KAIST researchers have developed a new therapeutic approach that uses hydrogen peroxide (H₂O₂), a reactive oxygen species that damages cells and increases in the brains of patients with Alzheimer's disease, to activate a drug selectively in diseased brain tissue. The team also confirmed improvements in cognitive function through animal experiments, presenting a new possibility for next-generation dementia treatment.
KAIST (President Kwang Hyung Lee) announced on the 2nd that a research team led by Professor Mi Hee Lim of the Department of Chemistry, in collaboration with Professor Mingeun Kim of Chonnam National University, Dr. Chul-Ho Lee and Dr. Kyoung-Shim Kim of the Korea Research Institute of Bioscience and Biotechnology, and Dr. Young-Ho Lee of the Korea Basic Science Institute, has developed a prodrug that is activated selectively in the diseased brain in Alzheimer's disease and confirmed its therapeutic effects through animal experiments.
A prodrug is a drug that initially has minimal therapeutic effect but is converted into an active therapeutic agent only under specific conditions inside the body. In this study, the prodrug was designed to be activated only when it encounters hydrogen peroxide, which increases in the brains of patients with Alzheimer's disease, allowing it to function as a "smart therapeutic agent" that selectively acts in diseased brain tissue.
In the brains of Alzheimer's disease patients, hydrogen peroxide, which damages cells, is elevated above normal levels. Until now, it has generally been regarded only as a harmful substance that should be removed. However, the research team devised a method to use it instead as a signal that activates a drug.
The prodrugs developed by the research team, BE-1 and BE-2, are designed to remain minimally reactive in a healthy brain. However, when they encounter hydrogen peroxide in a brain affected by dementia, they are converted into active therapeutic compounds, AP-1 and AP-2. Through this process, they reduce reactive oxygen species, including hydrogen peroxide, while also preventing amyloid beta (Aβ) peptides — peptides known as a major cause of dementia that accumulate in the brain and damage nerve cells — from aggregating into highly toxic clumps.
Using advanced analytical techniques, the research team confirmed that the activated drug alters the morphology of amyloid beta aggregates and suppresses their growth into large aggregates.
These effects were also confirmed in Alzheimer's disease mouse models. The drug crossed the blood-brain barrier (BBB), a protective barrier that controls whether substances in the blood can enter the brain, and was converted into the therapeutic compound inside the diseased brain. In mice that received long-term drug administration, oxidative stress in the hippocampus, which is responsible for memory, was reduced, and amyloid beta accumulation in the brain also decreased. In behavioral experiments assessing the ability to recognize new objects and navigate mazes, cognitive function was also found to improve.
This study is significant in that the drug was designed to operate only where needed by using the environment of the diseased brain itself. This approach presents a new strategy for dementia treatment that can enhance therapeutic efficacy while reducing side effects, and it is expected to be applicable to the treatment of other neurodegenerative diseases, such as Parkinson's disease.
Professor Mi Hee Lim of KAIST's Department of Chemistry said, "This study is meaningful in that hydrogen peroxide, which had previously been regarded only as something to be eliminated, was used as a signal to activate a drug. We expect this strategy, which activates drugs in diseased tissue, to become a new platform for treating complex diseases such as Alzheimer's disease more safely and effectively."
This study was co-first-authored by Jimin Lee and Eunseo Hong, Ph.D. candidates in KAIST's Department of Chemistry, and was published online on May 31, 2026, in the international journal Small (Impact Factor: 12.1, top 10% in the field of chemistry).
※ Paper title: A Prodrug Approach for Activity-Based Chemical Modulation toward Multiple Pathological Targets in Alzheimer's Disease
DOI: 10.1002/smll.74013
This research was supported by the National Research Foundation of Korea's Leader Researcher Program, Global Leading Research Center Program, Sejong Science Fellowship, Graduate Student Research Encouragement Program, and institutional programs of KRIBB and KBSI.
