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The Skaggs Institute for Chemical Biology
Scientific Report 1999-2000


Bioorganic Chemistry


J.W. Kelly, A. Angeles, H. Bekele, S. Deechongkit, M.B. Huff, M. Jäger, X. Jiang, E. Koepf, J. Kowalski, R. Kaul, H. Lashuel, V. Oza, H.M. Petrassi, E. Powers, H. Purkey, P. Raman, G. Ratnaswamy, H. Razavi, F. Schneider, T. Walkup, J. White, L. Woo

The central theme of our research is the development of research projects that are innovative, somewhat risky, and have the promise of significant return.

Synthesis of Oxazoline- And Thiazoline-Based Heterocycles

During the past year, we developed titanium-based chemistry that activates the amide oxygen toward displacement by the side-chain nucleophile (e.g., oxygen, sulfur) to yield oxazoline- and thiazoline-based heterocycles with retention of stereochemistry at both the α and ß carbon atoms. We generated reagents that produce oxazolines or thiazolines in starting materials capable of yielding both compounds and reagents that yield mixed fused heterocylces. We are developing both solution and solid-phase parallel synthesis methods to prepare natural products and their analogs; compounds related to the natural products and analogs have anticancer, antibiotic, and RNA-binding activity. We are also creating automated screening methods that should be useful for discovering alternative reagents for the synthesis from simple peptides of several fused heterocyclic ring systems that lack amide bonds.

Self-Assembly of Surface-Active Peptides and Peptidomimetics

From earlier published work, we suspected that some of the peptidomimetics we developed that form monolayers at the air-water interface do so spontaneously; no application of the peptide to the water surface in an organic solvent and compression of the monolayer with a moving barrier is involved. Indeed, we discovered a class of peptides that prefer the air-water interface over the aqueous solution even though the peptides are quite soluble. Furthermore, the peptides spontaneously self-assemble at the surface into 2 different ß-sheet quaternary structure-based phases in the absence of a compressive force. Peptides and peptidomimetics that can be dissolved in water and lead to interfacial ß-sheet quaternary structures should be interesting for a variety of surface science and technology applications, including facilitating the crystallization of high-value solutes.

Small-Molecule Inhibitors In Protein Misfolding and Aberrant Proteolytic Processing In the Endoplasmic Reticulum

Gelsolin amyloid disease is characterized by peripheral neuropathy and is due to a mutation at position 187. The mutation appears to lead to misfolding and 2 endoproteolytic cleavages, yielding a secreted 71-residue, largely unstructured peptide instead of a 6-domain folded protein. Biophysical studies on a slightly larger folded construct indicated the influence of these amyloidogenic mutations in destabilizing domain 2, resulting in formation of amyloid fibrils. Gelsolin amyloidogenesis appears to be due to the ability of domain 2 to sample the unfolded state during secretion, enabling proteolysis. We discovered inositides that bind to and stabilize this domain in vitro, and we are synthesizing compounds that we think will work in living cells in culture.

Publications

Crane, J.C., Koepf, E.K., Kelly, J.W. Mapping the transition state of the WW domain ß-sheet. J. Mol. Biol. 298:283, 2000.

Klabunde, T., Petrassi, H.M., Oza, V.B., Raman, P., Kelly, J.W., Sacchettini, J.C. Rational design of potent human transthyretin amyloid disease inhibitors. Nat. Struct. Biol. 7:312, 2000.

Lashuel, H.A., LaBrenz, S.R., Woo, L., Serpell, L.C., Kelly, J.W. Protofilaments, filaments, ribbons and fibrils from peptidomimetic self-assembly: Implications for amyloid fibril formation and materials science. J. Am. Chem. Soc., in press.

Petrassi, H.M., Klabunde, T., Sacchettini, J.C., Kelly, J.W. Structure-based design of N-phenyl phenoxazine transthyretin amyloid inhibitors. J. Am. Chem. Soc. 122:2178, 2000.

 

 







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