Continuing their highly productive (32 publications), 20-year collaboration, Professor Karen Allen and Dr. Debra Dunaway-Mariano, University of New Mexico, have received a 4-year, $1.26 million award from the NIH. The team is known for much of the current understanding of catalysis and specificity of the Haloalkanoic Acid Dehalogenase Superfamily (HADSF). This current award, “Structure and Function of HAD Phosphatase Partners Dullard and Lipin,” represents a new and highly innovative research direction for the the Co-Investigators. Using an interdisciplinary approach, they will investigate the structural basis for the function of two enzymes that utilize the same protein scaffold to interact with and dephosphorylate macromolecules and phospholipids at the cell membrane. The Co-Principal Investigators bring their respective expertise to address the problem. Karen Allen will direct the protein chemistry, bioinformatics, X-ray crystallographic and Small-angle X-ray Scattering aspects of this project. Debra Dunaway-Mariano will direct the substrate screening, assay development, and radio-labeled vesicle binding studies.
By defining the structural features of enzymes that allow recognition of specific proteins and cell membrane components, the study will provide significant insight into the complexities of cell lipid metabolism. The findings will lay the foundation for the rational design of therapeutic agents to treat the diseases associated with diabetes and clinically identified defects in fat metabolism.
The NSF Division of Chemical, Bioengineering, Environmental, and Transport Systems (CBETS) has funded Bjoern Reinhard and his Co-Investigator, Professor Luca Dal Negro (Electrical & Computer Engineering,) to combine the advantageous photonic and plasmonic properties of nanostructured surfaces to develop a multiparametric responder that improves sensitivity and selectivity of conventional biosensing platforms through combined analysis of elastic and inelastic light-scattering processes. The award, “Multiparametric Optical Sensing of Microbes on Plasmonic Nanostructures,” is for $300K over three years.
Professor Larry Ziegler and his group have received continued support from the NSF ($450K over 3 years) to use cutting edge spectroscopic techniques to advance understanding of supercritical fluids (SCFs) as a medium for chemical activity. Using ultrafast vibrational or rotational spectroscopic techniques, they will study the femtosecond to picosecond solvation dynamics of a range of SCF solutions as a function of density for isotherms close to the critical temperature. The insights gained will identify those solvent motions coupled to the spectroscopically tagged solutes in the femtosecond to tens of picoseconds regime providing a dynamical description of solvation in the compressible fluid regime of SCFs. Such dynamics are important to understand, because they are intimately involved in the unique microscopic solvation phenomena that give super critical fluids their interesting and useful properties. Given the very high relevance of supercritical liquids for applied chemistry on the one hand and the lack of detailed knowledge on their microscopic dynamics on the other, this research is expected to provide new and important insight into structural fluctuations and local interactions governing solvation processes and, thus, chemical dynamics.
Professor Corey Stephenson and his group have received a 5-year, $1.7 million award from the National Institutes of Health (NIGMS) to develop novel catalytic approaches to the synthesis of alkaloid natural products. These visible light-mediated methods provide innovative avenues toward challenging molecular architectures with broad biological activity.
The Stephenson Group focuses on performing syntheses in an environmentally conscious way. By using visible light, they prepare waste-free, non-toxic “reagent” complex natural products. Since most organic molecules do not absorb visible light, they can use photosensitive catalysts (widely studied for their photophysical properties) to carry out transformations under mild conditions in the presence of otherwise reactive functional groups. These new chemical reactions will enable the synthesis of biologically active natural products implicated in cancer, infection, and cardiovascular disease.
There are many medically important drug targets that current drug discovery technology is not able to address. Collaborative basic research in Chemistry, Biology, and Biochemistry is key to solving these intractable problems to enable the discovery of new classes of drugs. A multidisciplinary team at Boston University, led by Associate Professor of Chemistry Adrian Whitty, aims to develop new approaches for challenging molecular targets. The National Institute of General Medical Sciences awarded this team a 4-year, $1.6 million grant entitled Design of Macrocyclic Inhibitors of the NEMO/IKKα/β Protein-Protein Interaction.
Only about 10% of the potential drug targets in the human genome have been successfully targeted with marketed drugs. Of the remaining 90%, many are intracellular proteins whose function is critically dependent on their reversible interactions with other proteins. Despite decades of effort by the pharmaceutical industry, developing oral drugs that inhibit protein-protein interactions (PPIs) has rarely succeeded and has become recognized as a major scientific and technological challenge.
The primary goal of this project is to determine whether the use of a class of natural product-inspired compounds called macrocycles constitutes a broadly applicable method for developing oral drugs against PPI targets. As a first challenge, the team is attempting to develop macrocycles that block the activity of NEMO, a key component of the IKK complex that activates NF-κB signaling. Chronic hyperactivity of the NF-κB pathway is associated with many human inflammatory diseases and cancers. Thus, the development of drug-like inhibitors of this pathway is highly relevant to public health.
The work will determine whether appropriately designed synthetic macrocycles can inhibit PPI targets while maintaining good drug-like properties. In terms of NF-κB and disease, their work will provide a means for testing whether inhibiting the interaction of NEMO with IKK—as a more targeted alternative to completely ablating all IKK activity—represents a useful new approach for attenuating inflammation.
In addition to Professor Whitty (quantitative biochemistry and drug discovery), the multidisciplinary research team comprises Professors Sandor Vajda and Dima Kozakov (computational chemistry), John Porco and Aaron Beeler (macrocycle synthesis), Karen Allen (X-ray crystallography), and Tom Gilmore (NF-κB pathway biology).