In 1999, Dr. Tang's research team identified a human brain protease called memapsin 2, which turned out to be a key player in the pathological cascade leading to Alzheimer’s disease. Alzheimer’s disease inflicts 18 million people worldwide, and this number is projected to be about 24 million by 2025. It is a major cause of death for adults, yet there is no effective drug that can slow or stop the progression of the disease. Therefore, finding memapsin 2 provided a new target for the design and testing of inhibitors that may someday be used as a drug to treat Alzheimer’s disease.
The development of such a drug was a great challenge. Such an inhibitor must stop memapsin 2 from functioning but not stop other important functions or related normal enzymes of the body. It must be small enough to be taken up by the intestine and must move across many natural barriers in the body to reach the brain in order to exert its action. There is no hope of developing such a drug until much is known about memapsin 2. In the two-year period of 2000 to 2001, Tang and his colleagues meticulously documented all the required basic information and developed the technologies with which the development of an inhibitor drug became possible. One of their most important discoveries was the determination of the three-dimensional shape of the memapsin 2 region, called the active site, where the inhibitors are targeted to occupy.
Thus the stage was set to design inhibitors to fit the memapsin 2 template. Once that happened, creating the best drug properties (absorption, penetration into the brain, etc.) could be investigated. The drug design and testing began as an NIH-supported research project in my laboratory. The inhibitors designed initially showed enormous promise. It became obvious that a major drug development project was underway. However, such a project would greatly exceed the scope and resources of the NIH research project. With the help of OMRF, a biotech/pharmaceutical company was founded in 2002 to drive the drug discovery process. Zapaq received initial seed funding from Oklahoma Life Science and the Institute for the Study of Aging in New York and later venture funds from Sanderling, which is located in the bay area near San Francisco, at a total of about $15M. Today, Comentis (formerly Zapaq) is where advanced memapsin 2 inhibitors are being developed. The company has taken a drug candidate to phase I clinical trials.
Meanwhile, the basic research on memapsin 2 progressed in Tang's laboratory at OMRF. Besides exploring memapsin 2 structure for new ways to design better inhibitors, they studied what memapsin 2 does in normal people and in those with Alzheimer’s disease. This is an important area of investigation, as the more we know about the physiological role of memapsin 2, the better we will be able to control the therapeutic strategy when there is an inhibitor drug against it.
Alzheimer’s disease inflicts itself upon 18 million people worldwide and may affect up to 24 million by 2025. It is a major cause of death for adults, yet no effective drug exists to slow or stop the progression of the disease. In 1999, Dr. Tang and his colleagues identified a protease called memapsin 2, or beta-secretase, a brain protease which initiates a selective proteolysis of beta-amyloid precursor protein (APP) leading to the production of amyloid-beta (Aβ). The accumulation of Aβ in the brain is a major factor in the pathogenesis of Alzheimer’s, so memapsin 2 has emerged as a major target for the development of inhibitor drugs to treat the disease. In recent years, Tang studied the structure-function relationships of memapsin 2, including the specificity, crystal structure and the development of potent first-generation inhibitors. These are basic tools that enable inhibitor development.
A major effort lay in the design, synthesis and testing of new generations of memapsin 2 inhibitors with clinical potential. Results from basic studies permitted Tang to use structure-based design cycles. In this approach, his lab used crystal structures of memapsin 2 complexed with inhibitors to gain insights and to produce better next generation inhibitors. Such studies brought about small, potent and selective inhibitors capable of inhibiting memapsin 2 in biological systems.
Tang also attempted to understand the regulation of memapsin 2 in physiological and pathological settings. Since memapsin 2 is an aspartic protease that optimally functions in an acidic environment, its internalization from cell surface to endosomes is important in cellular trafficking for the hydrolysis of APP. Tang discovered that the endocytosis of memapsin 2 is facilitated by its association with APP, while recycling of memapsin 2 is mediated by various factors, including GGA, retromer and the phosphorylation of memapsin cytosolic domain. It seemed likely that these processes are involved in the regulation of Aβ production and the pathogenesis of Alzheimer’s disease.
Together, Tang's studies will hopefully lead to the design of memapsin 2 inhibitor drugs for Alzheimer’s disease, a better understanding of the physiological functions of memapsin 2 and the consequences of its inhibition.
B.S., Taiwan Provincial College, 1954
M.S., Oklahoma State University, 1957
Ph.D., University of Oklahoma, 1961
Honors and Awards
1960 Two Physiology Fellowships, Marine Biological Laboratory, Woods Hole, MA
1964-1965 John Simon Gugenheim Fellowship
1969-1974 National Institutes of Health Career Development Award
1989 Honorary Professor, Chinese Academy of Sciences, Institute of Microbiology, Beijing, China
2000 Pioneer Award, Alzheimer’s Association
Editorial board of Journal of Biological Chemistry
Member of NIH Physiological Chemistry Study Section
Member of NIH AIDS Research Study Section
Organizer of four international scientific conferences in proteins and aspartic proteases
Research lectures at numerous international symposia
Lectures to graduate and medical students
International Advisor to Chinese Academy of Sciences Molecular Biology Laboratory
International Advisory Board to Acta Biochimica et Biophysica Sinica
American Society for Biochemistry and Molecular Biology
American Chemical Society
American Association for the Advancement of Science
Joined OMRF Scientific Staff in 1966.
(First joined OMRF in 1957.)
Wu H, Castanheira P, Faro C, Tang J. Cardosin A endocytosis mediated by integrin leads to lysosome leakage and apoptosis of epithelial cells. Proteins 87:502-511, 2019 June, PMID: 30785216
Ghosh AK, Brindisi M, Yen YC, Lendy EK, Kovela S, Cárdenas EL, Reddy BS, Rao KV, Downs D, Huang X, Tang J, Mesecar AD. Highly Selective and Potent Human β-Secretase 2 (BACE2) Inhibitors against Type 2 Diabetes: Design, Synthesis, X-ray Structure and Structure-Activity Relationship Studies. ChemMedChem 14:545-560, 2019 March, PMID: 30637955, PMCID: PMC6637425
Ghosh AK, Ghosh K, Brindisi M, Lendy EK, Yen YC, Kumaragurubaran N, Huang X, Tang J, Mesecar AD. Design, synthesis, X-ray studies, and biological evaluation of novel BACE1 inhibitors with bicyclic isoxazoline carboxamides as the P3 ligand. Bioorg Med Chem Lett 28:2605-2610, 2018 August, PMID: 29970308, PMCID: PMC6085084
Ghosh AK, Brindisi M, Yen Y, Xu X, Huang X, Devasamudram T, Bilcer G, Lei H, Koelsch G, Mesecar AD, Tang J. Structure-based design, synthesis and biological evaluation of novel beta-secretase inhibitors containing a pyrazole or thiazole moiety as the P3 ligand. Bioorg Med Chem Lett 2015. [Abstract] EPub
Ghosh AK, Brindisi M, Tang J. Developing β-secretase inhibitors for treatment of Alzheimer's disease. J Neurochem 120:71-83, 2012. [Abstract]
Chang WP, Huang X, Downs D, Cirrito JR, Koelsch G, Holtzman DM, Ghosh AK, Tang J. β-Secretase inhibitor GRL-8234 rescues age-related cognitive decline in APP transgenic mice. FASEB J 25:775-784, 2011. [Abstract]
Li X, Bo H, Zhang XC, Hartsuck JA, Tang J. Predicting memapsin 2 (β-secretase) hydrolytic activity. Protein Sci 19:2175-2185, 2010. [Abstract]
Ghosh AK, Kulkarni S, Anderson DD, Hong L, Baldridge A, Wang YF, Chumanevich AA, Kovalevsky AY, Tojo Y, Amano M, Koh Y, Tang J, Weber IT, Mitsuya H. Design, synthesis, protein-ligand X-ray structure, and biological evaluation of a series of novel macrocyclic human immunodeficiency virus-1 protease inhibitors to combat drug resistance. J Med Chem 52:7689-7705, 2009. [Abstract]
He X, Cooley K, Chung CH, Dashti N, Tang J. Apolipoprotein receptor 2 and X11α/β mediate apolipoprotein E-induced endocytosis of amyloid-β precursor protein and β-secretase, leading to amyloid-β production. J Neurosci. 27:4052-4060, 2007. [Abstract]
Protein Studies Research Program, MS 28
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