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Wetzler Group Research

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:

Background

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.

Submonomer peptoid synthesis

New Ways of PEGylating peptides
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.
Peptoid Structure and Folding
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.

Alanine peptoid synthesis

Novel Actinide Ligands
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.