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Assembly
and disassembly of peptides and proteins is a recurring theme
in the research of our group. Self assembly is an essential
element in the biological activity of biopolymers. In our
research we design and synthesize self assembling peptide
systems with novel binding and catalytic features. Our work
spans many areas of interest including:
· Covalent
Stabilization of Large Helical Bundles
· Peptide-Enhanced
Liposomal Drug Delivery
· Self-Replicating
Peptides
Work
in these areas has the promise of producing viable ways of
targeting drugs to the site of their action in the body, and
has the potential to answer fundamental questions on the nature
of the molecular origins of life.
Many proteins also associate to form dimers and larger assemblies.
The enzymes of HIV, for instance, rely on dimer formation
for optimum catalytic activity. Transcription factors also
form dimers, and this dimerization event is essential for
their specific DNA binding properties. We have prepared unique
inhibitors of dimerization in a number or areas including:
· Enzymes
of HIV: Protease and Integrase
· Transcription
Factors: E47, Fos/Jun, E2A-HLF, NF-kappaB
· Restriction
Endonucleases
Inhibitors
of this type may lead to potent classes of anti-AIDS or anti-cancer
therapeutic agents, and also provide an increased understanding
of the intermolecular contacts at protein subunit interfaces.
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Selected
Publications
•
R. Zutshi, J. Franciskovich, M. Shultz, B. Schweitzer, P.
Bishop, M. Wilson, J. Chmielewski, "Targeting the Dimerization
Interface of HIV-1 Protease: Inhibition with Crosslinked Interfacial
Peptides", J. Am. Chem. Soc., 119, 4841 (1997).
•
K. Vogel, S. Wang, P. Low, J. Chmielewski, "Peptide-Mediated
Release of Folate-Targeted Liposome Contents from Endosomal
Compartments" J. Am. Chem. Soc., 118, 1581 (1996).
•
S. Yao, I. Ghosh, R. Zutshi, J. Chmielewski, "Selective
Amplification via Auto- and Cross-Catalysis in a Replicating
Peptide System", Nature., 396, 447 (1998).
HIV
protease monomer (white) with bound synthetic inhibitor.
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