1985 — 1986 |
Moeller, Kevin D |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Cyclopentane Synthesis Via the Oxy-Cope Rearrangement @ University of Wisconsin Madison |
0.939 |
1991 — 2018 |
Moeller, Kevin Buhro, William [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Intramolecular Anodic Olefin Coupling Reactions
In this project funded by the Chemical Synthesis program of the Chemistry Division, Professor Kevin Moeller of the Department of Chemistry at Washington University in St. Louis will explore the chemistry of highly reactive radical cation intermediates and the molecular transformations that they trigger. The radical cation intermediates are generated electrochemically, a versatile technique that allows for structure-reactivity studies to be conducted on the radical cations. These studies serve to increase our mechanistic insight into the factors that control radical cation initiated reactions, and in so doing open up the opportunity to discover new synthetic methods for the construction of complex organic molecules.
Since the electrochemical methods being developed can be conducted with the use of sunlight as the source of electricity, the chemistry holds great potential as a sustainable method. For example, chemical oxidation reactions utilize stoichiometric amounts of a chemical oxidant and in so doing require the formation of a stoichiometric reduction product as waste. In contrast, electrochemical oxidation reactions do not employ a chemical oxidant. Instead, the oxidation occurs by the loss of an electron to an anode surface. The required reduction reaction is channeled toward the formation of hydrogen gas at the cathode. Hence, a solar-driven electrochemical oxidation consumes only sunlight and generates hydrogen as the only byproduct. The proposed research will seek to expand this approach as a general synthetic method. Finally, this project will provide an excellent training environment for students, from pre-undergraduate to graduate, including those from historically underrepresented in the sciences.
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1 |
1996 — 1999 |
Moeller, Kevin D |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
New Tools For Probing Peptide-Protein Interactions
Seven-transmembrane (7-TM) receptors are found throughout the body and count among their members the primary targets for most neurotransmitters and peptide hormones. Due to the large number of 7-TM receptors and the flexibility of most 7-TM ligands, many agonists for a particular 7-TM receptor site have the ability to bind and activate numerous other sites and hence give rise to a variety of side effects. Clearly, an understanding of what factors govern the binding of hormones to particular 7-TM receptors is essential for developing potential drug candidates that can discern between related receptor sites. The proposed research aims to examine the overall utility of a series of lactam-based, conformationally constrained peptide mimetics for "mapping" the three-dimensional requirements of 7-TM receptors. Specifically, the thyrotropin releasing hormone 7-TM receptor TRH-R and the substance P 7-TM receptor NK1 will be studied. In both cases, a pair of models exist for the conformation of the hormone responsible for binding, and in both cases conformationally restricted analogs capable of differentiating between the models have been designed. In the proposed work, these restricted analogs will be synthesized and tested for both their affinity and potency for the appropriate 7-TM receptor. The biological data will then be used to draw conclusions about the receptor bound conformation of the hormone. One of the key problems in any such study involves the synthesis of the desired constrained analogs. Many studies of this nature fail when the required analogs can not be made. Even when the analogs are synthesized, if the syntheses are too complex, then the general applicability of the approach is severely limited. Since the long range objective of this work is to develop generally useful strategies for probing the relationship between the predicted and actual biological activity of peptide conformations, one of the primary objectives of the proposed research will be to develop new synthetic methodology for rapidly constructing lactam- based peptide mimetics.
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1 |
1997 — 1998 |
Moeller, Kevin D |
P41Activity Code Description: Undocumented code - click on the grant title for more information. |
(Nih) Novel Synthetic Approaches to Rigid Peptide Analogs
proteins; spectrometry; biomedical resource; biological products;
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1 |
2003 — 2009 |
Moeller, Kevin |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
New Synthetic Methods For Building Chip-Based Libraries
This project is focused on the development of chemistry needed for the site-selective preparation of molecules next to the electrodes in chip-based, addressable microarrays. Further studies of the reagent synthesis/confinement strategies developed in the previous funding period, site-selective use of Lewis acids in microarrays, and strategies to construct core molecular scaffolds will be performed. In addition to these synthetic efforts, new polymers and linkers for attaching small molecules to the surface of a microarray, utility of the microarray for determining relative binding constants for the molecules in a library with an added biomolecule will also be investigated.
With this award, the Organic and Macromolecular Chemistry Program is supporting the research of Professor Kevin D. Moeller of the Department of Chemistry at Washington University. Professor Moeller s research efforts revolve around the efficient preparation of molecular libraries (collection of target compounds) in chip-based, addressable microarrays. Libraries in such format have significant applications in biomedical research, as they could be used to identify target gene products with the tiny amounts of material generated by biological systems. Ability to prepare libraries in such microarray format is also important for developing materials with novel properties.
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0.915 |
2006 — 2011 |
Moeller, Kevin D |
P41Activity Code Description: Undocumented code - click on the grant title for more information. |
Synthesis of Electrochemical Entities |
1 |
2009 — 2013 |
Moeller, Kevin |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
New Synthetic Methods For Building Chip Based Libraries
This work will continue the development of microelectrode arrays as tools for probing interactions between small molecule libraries and biological receptors. The use of the microelectrode arrays allows for interactions between small molecules and biological receptors to be probed in "real-time" without the need for the subsequent washing steps typical of current state-of-the-art methods. In this way, more accurate information can be gathered about the three dimensional binding preferences of the receptor being studied. During the upcoming budget period, new site-selective chemistry that extends the general synthetic capabilities of the arrays will be explored. This work is essential because it is the synthetic methodology available for building molecules proximal to the microelectrodes in an array that defines both types of molecules that can be synthesized on the arrays and the nature of the biological problems that can be studied using them. Efforts will also be made to develop new polymer coatings for the microelectrode arrays that are compatible with the synthetic methods being discovered, to design and synthesize new linkers for attaching molecules to the polymer coatings so that the members of a molecular library on the arrays can be readily characterized, and to optimize the signaling capabilities of microelectrode arrays.
With this award, the Organic and Macromolecular Chemistry Program is supporting the research of Professor Kevin D. Moeller of the Department of Chemistry at Washington University in St. Louis. Professor Moeller's research involves the development of electrochemical methods for synthesizing organic molecules and probing their biological activity. The long-range impact of the proposed work will be to greatly enhance our ability to map the three-dimensional binding motifs of therapeutic targets and more effectively guide the design of new ligands and potential therapeutic agents for them. In this effort, microelectrode arrays will be developed and employed as tools for following the interactions between molecules and their targeted receptors as they happen. Successful accomplishment of this project will have a positive impact on the pharmaceutical and biotechnology industries.
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0.915 |
2013 — 2017 |
Moeller, Kevin Buhro, William [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
The Development of Microelectrode Arrays as Bioanalytical Tools
1262176 Moeller
Microelectrode arrays are potentially powerful tools for monitoring interactions between small molecule libraries and biological receptors. They hold two main advantages over current state-of-the-art methods. First, they can be used to detect binding events as they occur without the need for a labeled receptor or immunological assay. The result is a cost effective, rapid method for analysis that enables the use of biological data to interactively guide the design and synthesis of new receptor ligands. Second, the microelectrodes in an array can be used to reclaim molecules from the surface of the electrodes. Hence, molecules in a library that give rise to a biological signal can be isolated and characterized. This allows for quality control of the library. With these advances in mind, new chemistry for the site-selective placement, manipulation, and monitoring of molecules on the surface of a microelectrode array have been developed. In this project we will further build up the repertoire of tools by developing chemistry for direct synthesis of molecular libraries, porous membranes that will cover electrodes to minimize nonspecific binding and will demonstrate proof of concept use of novel electrode arrays for screening small molecules.
General public statement: This project will develop technologies based on electrode arrays to enable creation and testing of drug candidate molecules. This technology is interesting in that it can be used at all stages from biomolecule synthesis to its release to screening of biomolecule-target interactions.
This project is being funded by the Nano-Biosensing Program in the CBET Division of the ENG directorate, with co-funding from both the Chemical Measurement and Imaging (CMI) Program and the Chemistry of Life Processes (CLP) Program in the CHE Division of the MPS directorate.
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0.915 |
2017 — 2021 |
Blumer, Kendall J [⬀] Moeller, Kevin David |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Pharmacological Targeting of Galpha Subunits in Disease
Project Summary/Abstract Therapeutic development in a broad spectrum of diseases often involves drugs that target G protein- coupled receptors (GPCRs). However, despite the importance of GPCRs in disease pathogenesis or progression, receptor-targeted drugs often have surprisingly limited therapeutic effect. One reason is that multiple GPCRs with redundant functions drive disease pathogenesis or progression, as occurs in Alzheimer's, inflammatory disorders and many cancers. Thus, effective therapy would require concurrent targeting of multiple GPCRs, which often cannot be achieved because drugs targeting certain GPCRs do not yet exist, or all disease-driving GPCRs have yet to be identified. In other diseases, including uveal melanoma, hormone- secreting pituitary tumors and ~10-15% of all cancers, pathogenesis is driven independently of GPCRs by constitutively active mutant G protein ?-subunits. Here, GPCR-targeted drugs are inappropriate because they cannot prevent activation of mutant G proteins. However, both types of therapeutic roadblocks could be overcome by pharmacologically targeting G proteins instead of GPCRs. In addition to their clinical/translational potential, pharmacological agents that directly target specific G proteins would be extremely valuable as probes in basic science. They would provide simple, fast, cheap and reliable tools to identify novel functions of G proteins in normal physiology and in animal models of many diseases, in contrast to conventional knockout or knockdown strategies, which are slow, expensive, or suffer from compensatory or off-target effects. Furthermore, understanding how pharmacological agents inhibit specific G proteins will reveal fundamentally new mechanistic principles that control G protein activity. Accordingly, this project aims over the long term to develop a panel of pharmacological agents, each of which directly and selectively inhibits specific G protein ?-subunit subtypes, and describe their mechanisms of action in detail. Its foundation is a pair of nearly identical cyclic depsipeptide natural products that are bioavailable, potent and highly selective inhibitors of the Gq/11 subfamily of G protein alpha-subunits. Using a combination of synthetic organic chemistry, computational biology and G protein functional assays, the project team will pursue Specific Aims that will: 1) determine how these molecules inhibit Galpha activation; 2) identify features of these inhibitors that determine potency, pseudo-irreversibility and Galpha selectivity; and 3) identify synthetic analogs of these inhibitors that target constitutively active Gq/11. These Aims are founded on preliminary data showing that: 1) the project team has established the first robust, scalable route for synthesizing analogs of these inhibitors, as required for preclinical and, eventually, clinical studies; 2) the naturally produced inhibitor potently targets cells driven by constitutively active mutant Gq/11; and 3) the naturally produced inhibitor works by a mechanism that can be adapted to every Galpha subtype.
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1 |
2018 — 2021 |
Moeller, Kevin David |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
New Methods For the Synthesis and Analysis of Addressable Molecular Libraries
Project Summary: Microelectrode arrays provide a unique, new method for monitoring binding events between small molecules and a biological target in ?real-time?. The method is inexpensive, easy to do using commercially available equipment, and does not require the labeling of either the molecules or the biological target being studied. In addition, the use of a microelectrode array combines that analytical capability with powerful synthetic capabilities that allow for the controlled construction and characterization of spatially addressable molecular libraries. The result is a unique opportunity to expand the utility of surface-based, ?real-time? signaling methods to include experiments that are otherwise impossible. With this said, there are still significant challenges that remain. The synthesis of libraries on an array still involves the placement of individual members of the library on the array by the electrodes using a limited number of reactions. This limits the size of a library that can be made. The analytical techniques on the arrays frequently amplify signals so there is a need to calibrate the arrays by controlling the concentration of ligands on the surface. How can this be accomplished without sacrificing the ability to characterize and tune the surface of the array. Finally, it is one thing to state that new synthetic capabilities afford new analytical opportunities, but what are these opportunities. It is the goal of the propose work to address these issues by pursuing three main objectives. First, new site-selective methods for parallel synthesis will be developed so that molecular scaffolds that are either placed or built on an array can be diversified directly on that array. In this way, larger libraries can be synthesized directly onto the arrays thus avoiding the time and expense of transferring them to an array one member at a time. Second, the methodology needed to generate concentration gradients of a ligand on the arrays will be developed. This will allow calibration of the arrays so that he data gathered can be compared with alternative methods and solution-phase data and analyzed for potential avidity events. Third, analytical experiments on the arrays will be combined with FRET studies to illustrate how the binding and cleavage events associated with a protease can both be monitored on the same experimental platform. These efforts will be combined with the development of strategies for probing the kinetics of a binding event on the arrays so that new mechanistic insights into the rate determine step of the binding/cleavage process can be obtained. Accomplishing these aims will combine to illustrate how new synthetic methodology can expand the utility of microelectrode arrays and the types of problems to which they can be applied.
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