Chemical Biology Discussion Group: Special End-of-Year Meeting

Organizers: Virginia Cornish, Columbia University; Tarun Kapoor, The Rockefeller University

Recent years have seen an increasing level of dialogue between chemists and biologists, the lines of communication consolidated by the availability of recombinant biotechnology tools for manipulating the chemical structure of genes and the proteins they encode. This has led to an explosion of interdisciplinary activity at the chemistry/biology interface, now coined chemical biology. Meetings of this group provides a forum for lively discussion and for establishing connections and, perhaps, collaborations between chemists armed with novel technologies and biologists receptive to using these approaches to solve their chosen biological problem.

Program

James Rothman, Columbia University, "Approaches to High Throughput Cell Biology."

Qunzhao Wang, Albert Einstein College of Medicine, "Fluorescent Reporters of Protein Tyrosine Kinase Activity."

Lucas Gartenmann Dickson, Columbia University, "Defined Unnatural Oligomer Synthesis By the Translational Machinery."

Ross Chapman, New York University, "Synthesis and Biological Potential of the Hydrogen Bond Surrogate–Based Helices."

Justin Potuzak, Memorial Sloan–Kettering Cancer Center, "Stereocontrolled Synthesis of Spiroketals Using Novel Kinetic Cyclization Reactions."

Edmund Schwartz, TheRockefeller University, "Rapid In Vivo Activation of an Enzyme through Conditional Protein Splicing."

Abstracts

"Approaches to High Throughput Cell Biology"
James Rothman
It has taken about 50 years to functionate only 10 percent of the protein-coding genome with respect to health, and a much smaller fraction with respect to disease. Having the human genome sequence in hand provides an opportunity to accelerate discovery by orders of magnitude by the use of innovative, high-throughput techniques. The overwhelming challenge to genome science is now to understand how our approximately 25,000 protein-coding genes, through networks of regulation, create normal physiology, or disease. The scale of this "functionation" problem creates a pressing need for so-called "high-throughput" technologies capable of research on a scale that matches that of the genome.

"Fluorescent Reporters of Protein Tyrosine Kinase Activity"
Qunzhao Wang
Although the general role played by tyrosine kinases is well recognized, it is not trivial to decipher the contributions made by individual kinases to specific cellular actions. In particular, a common problem is the inability to directly correlate kinase action with some given cellular event of interest. We have developed a new mechanistic principle by which protein kinase substrates can fluorescently report the kinase-catalyzed introduction of a phosphate moiety. Sensors have been created for a wide variety of tyrosine kinases using an array of different fluorophores. Furthermore, a light-activatable ("caged") derivative of one of these sensors has been prepared, which allows the investigator to choose when the reporter is active and thus provides the means to sample kinase activity as a function of cellular events.

"Defined Unnatural Oligomer Synthesis By the Translational Machinery"
Lucas Gartenmann Dickson
Our long-term goal is to co-opt the translational machinery for peptidomimetic synthesis via synthetic acyl-tRNA building blocks. If successful, this research would allow complex small molecules to be synthesized in a one-pot reaction. The strength of this approach is that it allows DNA encoding of peptidomimetics and hence selections of very large library size (> 10¹²). As such, this research has the potential to substantially impact chemical synthesis and drug discovery in both industry and academia. With our 2003 Proc. Natl. Acad. S