Wetzler Group Research
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Note: Due to the rapdily evolving
nature of the research not all of the active research areas in the group
are currently described on this webpage. Please contact Dr. Wetzler for more
information.
Some of the main research directions in the lab include:
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Background
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Research in the Wetzler group focuses on rapid assembly of interesting
molecules for a diverse range of applications. Much, but not all, of the research
utilizes peptoids, a versatile class of peptide mimics that are extremely easy to
synthesize. Because of their extreme chemical diversity and modular construction
they lend themselves readily to a wide range of applications, including bioorganic
and medicinal applications, fundamental studies of structure and folding, inorganic
chemistry, nanoscience, and supramolecular chemistry.
Peptoids (N-substituted polyglycines) are synthesized using a submonomer
method that separately installs the carboxylic acid and amine parts of the amino acid
residues, (see Figure 1). The haloacetic acid and amines are often very soluble
and inexpensive, thus enabling use of many equivalents that drive each reaction to
very high rates of completion, and enable synthesis of long peptoids with great
amounts of chemical diversity in the side chains.
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New Ways of PEGylating peptides
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Peptide drugs are rapidly growing in importance and include the generally
biologically produced insulins (insulin glargine, insulin aspart, insulin
detemir, and insulin lispro) and the non-insulin peptide blockbuster (>$1B
annual sales in US) liraglutide. Both insulin detemir and liraglutide are
modified with non-biological side chains to improve their pharmacokinetic/
pharmacodynamic properties, demonstrating the needs for such non-natural
modification. With protein drugs the most common such modification is PEGylation.
The first PEGylated protein therapeutic, ADAGEN, was FDA approved in 1990, and
protein PEGylation is a mature technology with a dozen FDA approved drugs and
dozens more in clinical trials. Peptide PEGylation, in contrast, is not a
mature technology with no FDA approved examples. We have developed a new way
of PEGylating peptides that is very easy and straightforward to carry out,
and are applying this strategy to metabolically important peptides. This
work is presently in the process of being patented and thus no further details
are available at this time.
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Peptoid Structure and Folding
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Peptoids are poly-substituted glycines, and glycines are the most flexible and
secondary-structure breaking amino acids that exist. Consequently, peptoids are
not typically highly structured, and much effort has been devoted to identifying
ways of modifying peptoid side chains to make them more structured. In practice,
a very large percentage of the peptoid side chains need to be devoted just to
inducing structure, and that structure is often molten-globule-like. In contrast,
the Wetzler group is interested in modifying the backbone of peptoids;
specifically, since alanine is highly structured, we are working on the synthesis
and structural characterization of alanine peptoids (see Figure below). In alanine
peptoids, the alanine side chain would induce secondary structure formation, and
the peptoid side chain would provide function. This work is being conducted
in concert with a computational chemist, Prof. Brian Dominy in the Chemistry
Department at Clemson, an expert in molecular mechanics.
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Novel Actinide Ligands
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We are using multiple ligand classes as an entry point into targeting the actinyl ion,
primarily uranyl, the form of uranium found in blood, seawater, and nuclear waste.
Given the prevalence of the uranyl cation, a selective ligand for uranyl would enable
transformative advances in: (a) actinide decorporation agents that would be useful
in case of accidental or intentional exposure to actinides (no current actinide-specific
decorporation agents are approved in the US); (b) mining of the billions of tons of
uranium from seawater (the world's top uranium miner, Kazakhstan, sells almost
exclusively to China, and the price of uranium has gone up almost 10x in the past
two decades); and (c) the separation (and recovery) of the uranyl ion from the 270,000
tons of high-level nuclear waste. This work is being conducted in collaboration
with Profs. Brian Powell (actinide chemist) and Lindsay Shuller-Nickles (computational
actinide specialist) in the Environmental Engineering & Earth Sciences Department
at Clemson.
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