To date, only a very small fraction of proteins encoded by the human genome have been targeted by clinical drugs. To reduce morbidity and mortality of existing and newfound diseases, there is a fundamental need to develop new pharmaceutical agents and identify novel biological targets for therapeutic and preventative interventions. In the field of chemical genetics, bioactive organic molecules have been extensively used to model and understand biological systems. As our understanding of both organic chemistry and biology has increased, organic synthesis has also begun to extend its application from making compounds in flasks to directly addressing problems in biology. Along these lines, our research aims at developing molecular tools derived from underexploited classes of compounds with unknown mode of action, as well as applying organic reaction methodology, to interrogate cellular functions of bio-macromolecules, in particular proteins. This knowledge will then provide a solid ground for the rational design of novel bioactive agents with improved efficacy.
Synthetic organic/medicinal chemistry is our core science; however, our strategy will also involve techniques from mass spectrometry-based proteomics, molecular biology, and cell biology.
Project 1. Explore Pharmaceutical Potential of Protein Translocation Using Ipomoeassin F-Derived Chemical Entities
Resin glycosides are plant-derived structurally unique natural products. To date, more than three hundred members have been isolated. Although resin glycosides have been considered effective components in many medicinal plants, the molecules have not been well studied either as chemical probes in biology or as lead compounds for drug discovery. Very recently, we discovered a resin glysocide, ipomoeassin F (Table 1), as a specific and tight Sec61α binder that strongly inhibits protein translocation. In the future, we will design and synthesize new chemical entities based on the scaffold of ipomoeassin F to help understand function of the Sec61 translocon more comprehensively. Such knowledge will be useful for addressing the concern of whether Sec61α can be a druggable target or its inhibitors alone will just be hopeless, non-selective general cytotoxins.
Project 2: Translational Research on Open-Chain Saponins