Current Research and Scholarly Interests
We are a multi-disciplinary research lab that includes chemists, biochemists, biologists and physician scientists. We develop pharmacological agents and apply them to understand molecular and cellular events under basal and disease conditions using in vitro, in culture and in vivo models.
There are several research areas: two use peptide inhibitors and two to small molecules.
1. We study how protein-protein interactions govern cell signaling (Science, 1995). Using rational approaches, we identify short peptide inhibitors of intracellular protein-protein interactions to interfere with signal transduction under basal and pathological conditions (Nature Biotechnology, 2008). This rational approach led to the discovery of the only highly selective protein kinase C (PKC) inhibitors and activators. These peptide regulators of PKC identified the role of this family of enzymes in a number of cellular responses. Importantly, these peptide regulators are useful as therapeutics in a variety of animal models of human diseases, including myocardial infarction and heart failure (Nature Review Drug Discovery, 2013). A phase IIa study in humans demonstrated that one of the peptide inhibitors is efficacious in reducing cardiac damage in myocardial infarction patients. The study was carried out by KAI Pharmaceuticals that was co-founded with Dr. Leon Chen (a graduate student from the lab) in 2002. The company was acquired by Amgen in 2012 and one of KAI's drug was approved in Europe (2016). Current lab efforts focus on rationally generating substrate-specific inhibitors of the multi-substrate kinase, delta PKC (Qvit, J Am Chem Soc 2016; Qvit, Angewante 2016).
2. Recent effort focuses on rational design of inhibitors and activators of large GTPases that regulate mitochondrial dynamics (fusion and fission; Kornfeld, Circ Res 2015). One peptide inhibitor of pathological mitochondrial fission (Qi, JCS 2013; Guo, JCI 2013) is now being developed in Mitoconix (founded in 2016), as a treatment for Huntington's disease and other neurodegenerative diseases (Distanik, J Exp Med, 2016). Another peptide may provide a treatment for Charcot-Marie-Tooth II (Franco, Nature, 2016).
3. We unexpectedly identified aldehyde dehydrogenase 2 (ALDH2), the rate determining enzyme in ethanol metabolism, as a key regulator of cell survival under oxidative stress. We designed a novel assay to screen for activators of ALDH2, called Aldas (for ALDH activators) Science, 2008). Importantly, Aldas correct a structural mutation in ALDH2 found in ~0.5 billion East Asians and therefore represents a new class of drugs that serve as molecular chaperons (Nature Structure and Molecular Biology, 2010). Aldas also prevent nitroglycerin-induced tolerance and improves outcome after myocardial infarction(Science Translational Medicine, 2011). Very few selective activators of enzymes have been described. This research led to founding ALDEA Pharma with Dr. Che-Hong Chen, a senior scientist in the lab (2011); licensed to Foresee (2016). We also founded STAR, an international research organization for ALDH2 enzymopathy (Gross, Ann Rev Tox, 2015). Because defense from oxidative stress is determining cell survival, we examines the benefit of activating different ALDHs in a variety of diseases, including in Fanconi Anemia and radiation disease. Using a small molecule, we also 'hijacked' ALDH3A1 to metabolize the substrate of the mutated ALDH2 (Chen, PNAS, 2016).
4. Current efforts focus also on identifying small molecules that correct genetic defects in another critical enzyme for cell protection, glucose-6-phosphate dehydrogenase (G6PD). Mutations in G6PD lead to the second most common enzymopathy (~350 million people). Using high-throughput screening, in silico design and synthetic organic chemistry and X-ray crystallography, small molecule activators that increase the catalytic activity of the most common G6PD mutations are under development.
