New Mass Spectrometric Approaches Applied to Drug Discovery

Pieter C. Dorrestein, Ph.D.

Fellowship Director
Pieter C. Dorrestein, Ph.D.
Assistant Professor
UCSD Skaggs School of Pharmacy and Pharmaceutical Sciences
UCSD Departments of Pharmacology, Chemistry and Biochemistry

Research Background

Pieter C. Dorrestein is an assistant professor at the Skaggs School of Pharmacy and Pharmaceutical Sciences and the departments of Pharmacology, Chemistry and Biochemistry. In addition, he is a member of the Moores Cancer Center and the Center for Marine Biotechnology and Biomedicine at the Scripps Institution of Oceanography. Dorrestein currently has a 6.4T Thermo LTQ-FT-ICR-MS and MALDI-TOF system for use in his research program. Dr. Dorrestein’s research involves the use of novel mass spectrometric approaches, including imaging mass spectrometry and proteomic approaches to solve problems related to the biosynthesis of therapeutics of natural origin, develops of novel mass spectrometry based methods that enable the characterization of naturally occurring therapeutics, identify targets of natural products that are have therapeutic promise or that are already in the therapeutic development pipeline and his laboratory investigates the functional roles of novel post-translational modifications as a result of therapeutic stimulation.

For additional information on the research see Dr. Dorrestein's publication list at http://chem-faculty.ucsd.edu/dorrestein/Publications.html

Fellowship Program Objectives:

There are five main objectives in this fellowship:

  1. Characterize the function of novel post-translational modifications involved in the biosynthesis of therapeutics or that are good therapeutic targets themselves. This project combines the development of new mass spectrometric approaches with genomics to discover the function of enzymes involved in the biosynthesis of therapeutics. The main therapeutic areas of interest in this project are candidate acineoplastic agent, cholesterol lowering agents and anti-infectives.
  2. Develop new methods to characterize natural products from microbial systems, including pathogenic organisms involved in cell-to-cell communication. All cells communicate with other cells. There are no tools to systematically study the molecular output of a cell or even a small population of cells. This project aims to develop mass spectrometry based approaches to study the universal phenomenon of cell-to-cell communication.
  3. The development of approaches for the discovery of new promising therapeutics. ~75% of all anti-infectives and ~50% of all actineoplastics are or have origins in natural products. Microorganisms have the capability to produce many more therapeutic like molecules than we are currently capable of harvesting. For this purpose new mass spectrometric approaches will be developed to discover newly upregulated metabolites upon stimulation. A part of this effort also aims to overcome the supply issues of promising therapeutics.
  4. Therapeutic target identification, including off-targets. Target identification is very important to the drug discovery pipeline. Targets of promising marine natural products will be identified using chemical tagging and proteomic approaches in collaboration with other scientists at UCSD, UCSC, SALK, and SIO.
  5. Monitoring the global response of therapeutics by monitoring the signaling proteome. While a drug may have one or a few targets, the entire proteome of a cell or tissue will be affected. The phosphoproteome provides insight into the effect therapeutics have on cells or tissues and will be monitored upon drug stimulation. In this project we investigate the effect of therapeutics on signaling effects in a global proteomic fashion.

Coursework and training on:

  • Mass spectrometry and proteomics
  • Imaging mass spectrometry
  • Protein biochemistry
  • Natural product characterization.
  • Biosynthetic processes of therapeutics.

Unique skills fellows will acquire during the program

  • Learn laboratory skills such as microbial culturing, cloning, liquid chromatography, and mass spectrometry.
  • How to handle large a complex proteomic and imaging mass spectrometric data sets.
  • Interpretation of mass spectrometry data-sets.
  • Learn how to work collaboratively.
  • How to develop, execute and publish new science.

Time allocation: Two years