Assistant Professor of Biochemistry and
Adjunct Assistant Professor of Nutrition and Integrative Physiology and of Pharmaceutics
and Pharmaceutical Chemistry
B.S. National Taiwan University
Ph.D. Harvard University
Danny Chou's Lab Page
Danny Chou's PubMed Literature Search
Molecular Biology Program
Biological Chemistry Program
Diabetes, Insulin, Peptide and Protein Therapeutics, Chemical Biology
We focus on using synthetic protein engineering to create peptide or protein therapeutics with the goals to understand their biological effects in human diseases and improve clinical benefits in treating patients. Specifically, we use synthetic chemistry methods to introduce unnatural moieties into native proteins and peptides to generate analogues with enhanced properties. We are interested in tackling type 1 diabetes (T1D), an autoimmune disease in which the pancreas stops producing insulin, a hormone that enables glucose uptake from blood. By developing novel insulin and glucagon analogues, we hope to maintain normal blood glucose levels in type 1 diabetic patients.
Currently, we are focusing on the following research programs:
- New insulin and glucagon analogues for the use in artificial pancreas
- Glucose-responsive insulin or “smart insulin”
- Synthetic methodology for creating peptide and protein analogues
New insulin and glucagon analogues for the use in artificial pancreas
The artificial pancreas is a technology in development to help people with diabetes automatically control their blood glucose levels by providing the substitute endocrine functionality (insulin and glucagon) of a healthy pancreas. A continuous glucose monitor (CGM) senses glucose levels via a needle inserted under the skin. Based on these measurements, a dual-hormone pump injects either insulin or glucagon to maintain normal blood glucose levels. By automating detection of blood sugar levels and delivery of insulin/glucagon in response to those levels, an artificial pancreas has the potential to transform the lives of people with type 1 diabetes.
However, currently available fast-acting insulin analogues still have relatively slow absorption after subcutaneous injection, and the poor stability of currently available glucagon formulations necessitated daily replacement of the glucagon in the pump with freshly reconstituted material. In our lab, we focus on developing a next-generation ultrafast-acting insulin analogue that accelerates the insulin action and therefore mimics the physiological insulin action. We are also interested in developing stable glucagon analogues that stay fresh in dual-hormone pumps for at least three days.
Glucose-responsive insulin or “smart insulin”
Insulin analogues, either fast-acting or long-acting, have been demonstrated to improve glycemic control and reduce diabetes associated complications more than native insulin. However, although currently available insulin analogues reduce blood glucose levels, this blood glucose lowering action is not regulated in a glucose dependent fashion. The major consequence of excess insulin administration is hypoglycemia, because currently available injected insulin analogues remain biologically active, even when blood sugars are falling into dangerously low levels. Hypoglycemia therefore is the rate-limiting step in the glycemic management of diabetes. Hypoglycemia can lead to acute complications such as loss of consciousness, coma, and even death. On the other hand, insufficient insulin administration leads to inadequately treated diabetes that results in chronic hyperglycemia and complications such as blindness, kidney failure, and heart disease. There remains a need to modulate the kinetics of injected insulin therapy in vivo to more closely match the dynamics of fluctuating blood glucose levels that occur in vivo.
We are interested in developing glucose-responsive insulin or “smart insulin” such that its biological activity is regulated by the circulating glucose. Ideally, a “smart insulin” is a once daily administered drug that precisely delivers the required amount of insulin and, by responding to the circulating local glucose levels, will maintain normal glucose levels throughout the day. An estimated 2-10% of T1D patients will die of hypoglycemia and fear of this dire outcome prevents more aggressive blood glucose control. Therefore, the “smart insulin” represents a paradigm shift in T1D treatment and has the potential to improve the quality of life and save lives of T1D patients from acute hypoglycemia.
Synthetic methodology for creating peptide and protein analogues
Peptides and proteins have emerged as effective diagnostics and therapeutics in diseases including cancers, metabolic diseases, and autoimmune diseases. Synthetically modified peptide and protein analogues have demonstrated their potential to further enhance the properties of the native proteins. For example, PEGylated proteins improve the safety profile of the protein by shielding antigenic and immunogenic epitopes and reduce metabolic degradation. Despite these successes, synthetically modified peptide and protein derivatives remain underutilized. The complexity of protein structures usually leads to mixtures of protein derivatives and purification of the mixture is often challenging. A general platform for the synthesis and purification of modified peptide and protein analogues would enable the production of valuable protein molecules with new functions.
We aim to develop new methodology for high-throughput generation of peptide and protein analogues with unnatural segments. This could expedite the discovery of novel functional peptide and protein analogues and provide lead molecules for further optimization.
- Wang, Y.; Bruno, B. J.; Cornillie, S.; Chen, D.; Nogueira, J. M.; Cheathan, T. E.; Lim, C. S.*; Chou, D. H.-C.* “Application of Thiol-yne/Thiol-ene Reactions for Peptide and Protein Macrocyclizations” Chemistry- A European Journal, 2017, 29, 7087
- Chen, D.; Disotuar, M. M.; Xiong, X.; Wang, Y.; Chou, D. H.-C.* “Selective N-terminal Functionalization of Native Peptides and Proteins” Chemical Science, 2017, 8, 2717
- Menting, J. G.; Gajewiak, J.; MacRaild, C. A.; Chou, D. H.-C.; Disotuar, M. M.; Smith, N. A.; Miller, C.; Erchegyi, J.; Rivier, J. E.; Olivera, B. M.; Forbes, B. E.; Smith, B. J.; Norton, R. S.; Safavi-Hemami, H. & Lawrence, M. C. “A minimized human insulin receptor binding motif revealed in a venom insulin” Nature Structural & Molecular Biology, 2016, 23, 916-920
- Wang, Y. & Chou, D. H.-C.*. "A thiol-ene approach for native peptide stapling and macrocyclization" Angew. Chem. Int. Ed., 2015, 54, 10931
- Chou, D. H.-C*.; Vetere*, A.; Choudhary*, A.; Scully, S. S.; Schenone, M.; Tang, A.; Gomez, R.; Burns, S. M.; Lundh, M.; Vital, T.; Comer, E.; Faloon, P. W.; Dančík, V.; Ciarlo, C.; Paulk, J.; Dai, M.; Reddy, C.; Sun, H.; Young, M.; Donato, N.; Jaffe, J.; Clemons, P. A.; Palmer, M.; Carr, S. J.; Schreiber, S. L. & Wagner, B. K. “Kinase-independent small-molecule inhibition of JAK-STAT signaling” Journal of the American Chemical Society, 2015, 137, 7929-34
- Chou, D. H.-C.*; Webber, M. J.*; Tang, B. C.*; Lin, A. B.; Thapa, L. S.; Deng, D.; Truong, J.; Cortinas, A. B.; Langer, R. S. & Anderson, D. G. "Glucose-responsive insulin activity by covalent modification with aliphatic phenylboronic acid conjugates" Proceedings of the National Academy of Sciences, 2015, 112, 2401-2406
- Chou, D.H.; Holson, E.B.; Wagner, F.F.; Tang, A.J.; Maglathlin, R.L.; Lewis, T.A.; Schreiber, S.L. & Wagner, B.K. “Inhibition of histone deacetylase 3 protects beta cells from cytokine-induced apoptosis” Chem Biol. 2012, 19, 669-73
- Faloon, P.W.; Chou, D.H.C.; Forbeck, E.M.; Walpita, D.; Morgan, B.; Buhrlage, S.; Ting, A.; Perez, J.; MacPherson, L.J.; Duvall, J.R.; Dandapani, S.; Marcaurelle, L.A.; Munoz, B.; Palmer, M.; Foley, M.; Wagner, B. & Schreiber, S.L. “Identification of Small Molecule Inhibitors that Suppress Cytokine-Induced Apoptosis in Human Pancreatic Islet Cells” Probe Reports from the NIH Molecular Libraries Program, October, 2010 [updated 2011]
- Chou, D.H.; Duvall, J.R.; Gerard, B.; Liu, H.; Pandya, B.A.; Suh, B.C.; Forbeck, E.M.; Faloon, P.; Wagner, B.K. & Marcaurelle, L.A. “Synthesis of a novel suppressor of beta-cell apoptosis via diversity-oriented synthesis” ACS Med Chem Lett. 2011, 2, 698-702
- Chou, D.H.; Bodycombe, N.E.; Carrinski, H.A.; Lewis, T.A.; Clemons, P.A.; Schreiber, S.L. & Wagner, B.K. “Small-Molecule Suppressors of Cytokine-Induced beta-Cell Apoptosis” ACS Chem Biol. 2010, 5, 729-34
- Chao, T.-C.; Lin, Y.-T.; Yang C.-Y.; Hung T.-S.; Chou, H.-C.; Wu, C.-C. & Wong, K.-T. “Highly Efficient UV Organic Light-Emitting Devices Based on Bi(9,9-diarylfluorene)s” Adv. Mater. 2005, 17, 8, 992-996
- Anderson, D. G.; Chou, H.-C.; Webber, M. J.; Tang, B. C.; Levi, Y.; Zhang, Y.; Kanasty, R. L.; Vegas, A. J. & Langer, R. S. "Insulin Derivatives for Diabetes Treatment." WO2014093696 A2 (2014)
- Wagner, B. K.; Duvall, J. R. & Chou, D. H.-C. "Compounds and Methods for Treating Autoimmune Diseases." US20130317043 A1 (2013)