News and Publications
The Skaggs Institute for Chemical Biology
Scientific Report 1999-2000
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.
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
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.