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Microfluidics, the flow of liquids in micrometer sized channels, allows a reduction in reagent volumes and cost for biological and chemical assays. An emerging technology, microfluidic droplets, adds new functionality by confining reagents and cells in small droplets. The content of each droplet does not mix and therefore droplets can be considered test tubes of nanoliter volume. Droplets can then be used as microreactors for chemical reactions or can be analyzed sequentially or in parallel for large scale biological assays. However, techniques are needed to perform the basic chemical operations, such as mixing, addition and dilution, which would be typically carried out on the benchtop. Our group will work to expand the toolset for the control of microdroplets and use these tools for novel applications.
Tricyclic drugs long have been used in the treatment of various neurological imbalances. While much of the research in this area has been focused at the drug-receptor interface, it is important also to investigate drug interactions at the plasma membrane level, as it is necessary for these drugs to establish membrane interactions that favor their passage across membrane barriers, in order to accumulate in the nervous system in large enough quantities to elicit biological effects. Drug-membrane interactions can be divided into two categories: interactions promoting drug permeability, and interactions promoting drug retention (binding). Both types of interactions involve electrostatic interactions, though not much comprehensive data on either are available. In the proposed project the importance of membrane phospholipid composition in supporting the binding of a variety of tricyclic drugs will be examined.
As part of a research program aimed at studying how attached molecules affect the structure and function of peptides, we have recently synthesized several novel aminooxy amino acids.1,2 After their incorporation into peptides, these amino acids reveal side chains that can be reacted chemoselectively with reducing sugars to generate neoglycopeptides (Fig. 1). Importantly, our neoglycopeptides maintain biological relevance to natural glycopeptides because the sugars remain in their cyclic conformations and are close to the peptide backbone. Moreover, our strategy allows the facile combining of many different sugars with any given peptide. As a result, with a small amount of synthesis, we can create large numbers of neoglycopeptides.
Student projects will involve the synthesis of neoglycopeptide arrays and the subsequent use of these arrays to address biological issues of structure and function. The synthesis of the arrays exposes students to (1) the organic synthesis of novel amino acids, (2) solid phase peptide synthesis, and (3) sugar/peptide conjugation reactions along with extensive use of the analytical techniques of nuclear magnetic resonance (NMR), high performance liquid chromatography (HPLC), and electrospray ionization mass spectrometry (ESI-MS). The arrays will be used to address how attached sugars protect peptides from proteolysis, how they affect secondary structure, and how they affect the thermostability of peptides and small proteins.
Fig. 1. A chemoselective reaction for synthesis of a neoglycopeptide. The aminooxy group reacts selectively with the sugar in the presence of many other functional groups.
Research in my lab integrates techniques across chemistry and biochemistry. Our long-term research goal is to develop synthetic organic molecules called "peptoids" (N-substituted glycine oligomers) as artificial proteins for use in such applications as sensors, catalysts, and therapeutics. Like proteins, it is critical that peptoids adopt precise three-dimensional structural features to ensure proper function. While the preparation of peptoids is straightforward and efficient, it is much more challenging to characterize their structures. There is a need for new, efficient methods to assess peptoid structural features. Undergraduate research assistants in my lab prepare peptoids that are derivatized with a fluorescent dye or are functionalized to bind to a fluorescent dye. Then, we work to develop novel methods that correlate the presence of specific peptoid three-dimensional structural features with the peptoid's fluorescence emission. Ultimately, we will use screen thousands of unique peptoids attached to plastic resin beads to efficiently identify new peptoids with desired structural features. Peptoids identified in this way will be further characterized using other biophysical techniques, and their structures will be refined to accommodate a given application. Students in my lab will learn a variety of experimental techniques to address:
1. Synthesis, purification, and identification of peptoids.
Many chlorine-containing organic compounds, chloroform for example, are found at unacceptably high levels in drinking water reservoirs. We are attempting to find a way to catalyze the decomposition of these compounds with sunlight, starting with a metal complex that absorbs light, reacts with the chlorocarbon, and eventually is returned to its starting form by reacting with a compound containing an O-O-H group that is formed as part of the decomposition process of the chlorocarbon on its way to carbon dioxide.
HIV protease inhibition is an important pharmacological approach to combating the onset of AIDS in HIV infected patients. There are problems with this approach such as the development of resistant mutant virons and the cost of producing the present commercial medications. We are presently designing and building number of novel HIV protease inhibitors in my laboratory. These compounds differ dramatically from the previous inhibitors that have been described in the literature by utilizing a unique scaffold to present the important functionality in the correct 3-dimensional orientation in the HIV protease active-site. These protease inhibitors are straightforward to prepare and customize and should have comparable activity to known inhibitors. The ease of synthesis and the biological relevance of this research make it ideal for engagement of undergraduates. In designing a novel HIV protease inhibitor that is cost effective to prepare, we are hoping to address both the efficacy and distribution of these medicines. Presently, the high cost of these drugs practically prohibits treatment of HIV infected patients in the Third World. By redesigning these inhibitors to address this need, we hope to produce compounds that could lead to wider distribution of these pharmaceuticals.Development of Aptamer-Based Affinity Assays for Biologically Significant Small Molecules and Proteins
Steven W. Suljak, Ph.D., Analytical Chemistry (firstname.lastname@example.org)
Research in the Suljak laboratory is focused on developing strategies for chemical analysis utilizing aptamers, single-stranded DNA or RNA molecules that tightly bind specific target molecules. Our current efforts are aimed at identifying novel aptamers that can distinguish between proteins with particular post-translational modifications implicated in diseases such as cancer.
The research projects in the group is focused on investigating thermal and chemical behavior of molecules confined within small spaces. This is achieved by encapsulating small droplets within sub-micrometer sized polymer capsules, or by drawing the molecules into nanometer hexagonally aligned glass pores. The behavior of the molecules is studied using a variety of techniques, such as electron and atomic microscopy, differential scanning calorimetry and nuclear magnetic resonance spectroscopy.
We aim to use various biochemical techniques to understand the biological and environmental impacts of metal nanoparticles. The properties of nanomaterials differ substantially from bulk materials of the same composition; the reactivity of nanoproducts is complicated by small alterations in parameters such as shape and size. With the current data on nanoparticles, the bioavailability or toxicity for a given nanoproduct is essentially unpredictable. A mechanistic understanding of the bio-physicochemical interface of nanoparticles is essential for a sustainable increase of nanotechnologies in the marketplace.