The Shape of Things: Structure and Function in Chemical Biology

Organizers: Paramjit Arora, NYU; Derek Tan, Memorial Sloan Kettering Cancer Center

Speakers: Blake Peterson, Penn State University; Marc Greenberg, Johns Hopkins University; Peter Tonge, Stony Brook University

Abstracts

Synthetic Mimics of Mammalian Cell Surface Receptors: Blake Peterson

Receptors on the surface of mammalian cells promote the cellular uptake of proteins and other nutrients through the mechanism of receptor-mediated endocytosis. To mimic this process, we chemically synthesize artificial receptors that function as prosthetic molecules on the cell surface; they insert into cellular plasma membranes, project ligand-binding motifs from the cell surface, and enable cells to actively internalize cell-impermeable compounds. These synthetic receptors comprise the plasma membrane anchor N-alkyl-3beta-cholesterylamine linked to motifs that bind proteins and cell-impermeable drugs. When added to living mammalian cells, these prosthetic molecules rapidly cycle between plasma membranes and intracellular endosomes, promoting the delivery of ligands into intracellular compartments. Because of their ability to define new pathways across biological membrane barriers, synthetic cell surface receptors represent promising tools for drug delivery.

Recent Studies on DNA Damage And Repair Made Possible by Organic Chemistry: Marc Greenberg

As the carrier of genetic information, maintaining the structural integrity of the genome is critically important. Our goal is to understand how DNA is oxidatively damaged, what its effects are on the function of the biopolymer, and how enzymes guard against DNA damage. Organic chemistry provides the foundation in these investigations, and enables us to utilize the tools of biochemistry and molecular biology to study DNA damage and repair. These questions are approached by independently synthesizing oligonucleotides containing lesions or photolabile precursors to reactive intermediates that are involved in DNA damage. The oligonucleotides are used as tools in conjunction with a variety of chemical and biochemical methods. This approach has enabled us to uncover novel pathways for DNA damage (e.g. interstrand cross-linking), unambiguously elucidate the effects of specific lesions on replication and DNA repair in vitro and in E. coli, and unravel mechanistic questions. Recent advances in this area will be described.

Mycolic Acid and Menaquinone Biosynthesis: Mining the Magic Mountain for Novel Tuberculosis Drug Targets: Peter Tonge

The emergence of XDR-TB, a strain of Mycobacterium tuberculosis (MTB) that is resistant to first and second-line TB drugs, highlights the need for novel TB chemotherapeutics. We are currently developing inhibitors of fatty acid biosynthesis in MTB, focusing on two enzymes in the FASII pathway: KasA, the ketoacyl synthase and InhA, the enoyl reductase. In addition, we are also studying the biosynthesis of menaquinone, a lipid soluble component of the mycobacterial electron transport chain. We postulate that inhibitors of menaquinone biosynthesis may be active against latent TB, and the enzymology and inhibition of enzymes from this pathway will be discussed.