David Yue-Wei Lee, PhD

Unconventional approaches to investigating disease can bring unconventional breakthroughs. Dr. Lee’s Bio-Organic and Natural Products Research Laboratory explores and develops alternative treatments for substance abuse, autism, schizophrenia, Alzheimer’s disease, and other conditions.

Human disease is complicated and multifaceted. A single chemical entity targeted on one pathway or receptor is likely to have a limited therapeutic effect—in many cases relieving only the symptoms—and untoward side effects are common. By contrast, herbal remedies offer an opportunity to address simultaneously multiple biological pathways that might contribute to a disease or developmental condition. Dr. Lee’s research takes the accumulated knowledge of traditional Chinese medicine and uses a systemic biological approach that emphasizes balance in the entire organism. He seeks to develop evidenced-based herbal remedies by understanding the bioactive natural products and their modes of action to treat human disease—including chronic diseases for which there is no cure at the present time—in a comprehensive manner.

Dr. Lee’s group has extensive experience in the extraction and isolation of natural products using modern technologies such as preparative HPLC and high speed countercurrent chromatography. These products include a potent topoisomerase I inhibitor extracted from Boswellia caterii, a folk medicine used in the treatment of inflammatory diseases in India and China, several isoflavone C-glycosides for suppression of alcohol drinking in animals and humans, L-tetrahydropalmatine (L-THP) and its demethylated metabolite L-isocorypalmine (L-ICP) for treating cocaine addiction and other brain disorders such as schizophrenia, and Salvinorin A as the molecular lead for potent kappa receptor agonists.

The lab is also studying the optimization of drug leads from natural products via total synthesis or chemical modification. Allopregnanolone, the naturally occurring progesterone metabolite and a potent modulator of the GABA receptor, has profound effects on stress, anxiety, and alcohol- and drug-seeking behavior. Dr. Lee’s research has shown that certain synthetic analogs of allopregnanolone with improved half-life can stimulate chloride uptake in synaptoneurosomes, protect against bicuculline-induced seizures in alcohol-dependent rats, and reduce alcohol intake in alcohol preferring rats. Collectively, it appears that this class of compounds might yield potent GABA active agents with clinical significance.

Dr. Lee and his staff have shown that puerarin reduces alcohol consumption and eases withdrawal symptoms in animals and humans. They first reported the total synthesis of puerarin and discovered several synthetic analogs that are more potent than the parent molecule.

The lab also conducts bio-analytical and pharmacokinetic studies. They developed imaging agents for brain scanning—a technique that is rapidly expanding the reach of medical and scientific research—and also provide analytical chemistry support for clinical studies at McLean Hospital.