Our lab is interested in using organic chemistry as a tool to study problems in biology and materials science. The foundation of our interdisciplinary program lies in organic synthesis that allows for designing structures with tailored chemical function. In addition to synthetic techniques, students will be trained in a broad range of analytical, physical, and biological methods to probe the molecular details of their systems. Brief descriptions of three research areas currently pursued in the group are:
Nanoscale sensors using ion channel-forming peptides:
The goal of this research is to use natural and synthetic derivatives of ion channel-forming peptides to detect chemically and biochemically reactive agents. For instance, we recently demonstrated that an ion channel-forming peptide can be used to monitor the activity of enzymes on individual substrate molecules attached to near the opening of the pore. Detection is based on measurement of a change in the single ion channel conductance upon conversion of chemical groups on molecules attached near the opening of these semi-synthetic nanopores after exposure to specific enzymes in solution. This detection modality takes advantage of two-fold amplification (the catalytic turnover properties of enzymes and the amplification characteristics of ion flux through a single ion channel pore) to detect enzyme activity with high sensitivity. The ability to follow the conversion of substrate to product over time in the presence of different concentrations of enzymes made it possible to estimate the observed rate constant (kcat), the Michaelis constant (KM), and the catalytic efficiency of the enzyme using only picomolar concentrations of substrate and picomolar to nanomolar concentrations of enzyme. A major focus of this research is to develop simple and reliable methods to derivatize commercial ion channel-forming peptides in order to make these types of sensors available to the broader scientific community. We anticipate that ion channel-based sensors will offer advantages of higher sensitivity and similar specificity for detection of selected environmental or biological analytes compared to other currently available technologies.
Example of the detection of alkaline phosphatase (AP) activity using an ion channel platform. Here, AP catalyzes the time-dependent hydrolysis of a negatively-charged phosphate group on the gA derivative to a neutral alcohol. Shown below the schematic illustration are representative single ion channel recordings of the substrate and product, as well as the respective single channel conductance values, γ. We estimated the enzymatic conversion by measuring the fraction of single ion channel events corresponding to the product over time.
Molecular probes to study amyloid-based diseases:
We have been exploring potential functional properties of small, synthetic molecules that target aggregated forms of beta-amyloid (Ab) peptides for the development of new therapeutic and diagnostic strategies for Alzheimer’s disease (AD). A central hypothesis of our research is that aggregated forms of natural, disease-related peptides (e.g., aggregated AD-related Ab peptides) can cause cellular injury and, thus, play an important role in disease progression. We recently introduced the idea of generating molecular assemblies on the surface of aggregated AD-related peptides that could function as protein-resistive surface coatings on these disease-related materials. Current efforts in the group focus on the synthesis of small molecules that can attenuate the toxicity of aggregated forms of the Ab peptides on neurons either through inhibiting protein-amyloid interactions or through other Ab-neutralizing mechanisms. Related work also includes the development of in vivo imaging agents for the diagnosis and monitoring of Alzheimer’s and other amyloid-based neurodegenerative diseases.
Molecular surface coatings created on Alzheimer’s-related amyloid peptides prevent proteins from binding to the peptides. Shown are two examples of small molecules that create protein resistive surface coatings.
Nanoparticle-based cancer drug delivery systems:
The goal of this research is to develop new biocompatible, polymeric nanoparticles capable of improving the targeting of cancer therapeutics to solid tumors by controlling the location and time over which active drug release occurs. A central component of this research has been the development of a new class of acid-sensitive linkers that are designed to exploit the lower extracellular pH of some tumor cells, as well as the acidic environment of endosomes and lysosomes in cells, to trigger the controlled release of therapeutic agents from drug delivery vessels.