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 Porco Research Group has received a 4-year, $1.2 million award from the National Institutes of Health for their proposal, Chemical Synthesis of Bioactive Flavonoid and Xanthone-Derived Natural Products.
Undertaken in conjunction with biological collaborators, including Professor Tom Gilmore (BU Biology) and Dr. John Beutler of the National Cancer Institute’s Center for Cancer Research, the goal of the research is to develop new chemical methodologies to enable the synthesis of bioactive flavonoid and xanthone-derived natural products that could lead to biologically active antitumor and anti-infective agents. Specifically, such agents will be useful as novel pharmacological therapies and as cytotoxic agents against both human cancers and malaria.
Their aims include total syntheses of anticancer agents such as the kuwanons and related prenylflavonoid Diels-Alder natural products as well as the bioactive tetrahydroxanthones blennolides A and B.
The award enables an exciting new research direction for Professor Porco and his collaborators involving the use of nanoparticles in organic reactions, asymmetric catalysis, and novel cycloaddition strategies.
The Phi Beta Kappa’s Visiting Scholar Program (VSP) offers undergraduates the opportunity to spend time with some of America’s most distinguished scholars. It aims to contribute to the intellectual life of the campus by making possible an exchange of ideas between the Visiting Scholars and the resident faculty and students.
Professor John Straub is one of the 14 scholars selected by the 2011-2012 VSP Committee. Visiting eight schools (five in Fall 2011 and three in Spring 2012), he spends two days at each, giving a public lecture, meeting with undergraduates and faculty members, and participating in classroom discussions and seminars.
The schools on his itinerary are:
- Wake Forest University
- Florida State University
- Colorado College
- University of South Dakota
- Penn State University
- University of North Carolina at Greensboro
- Denison College
- Gettysburg College
Professor Straub’s research focuses on the development and use of mathematical and computational models to uncover the principles governing the fundamental processes of energy transfer, signaling, folding, misfolding, and aggregation that underlie protein function. His excellence as an educator has been recognized by Boston University by Gitner and Metcalf Awards. Committed to scientific outreach and communication, he has served as chair of the Theoretical Chemistry Subdivision of the American Chemical Society and as president of the Telluride Science Research Center, as well as on advisory panels to the Pinhead Institute, the National Science Foundation and the National Institutes of Health.
Their research provides strong evidence that Flavin Adenine Dinucleotide (FAD) plays a structural role in the formation of tetrameric AidB. While their studies clearly show FAD-dependent oligomerization of AidB, they do not address whether FAD also has a catalytic function. However, the picture of AidB that is emerging invokes a role for the DNA-binding domain in localization of AidB to specific genes, while the protective function appears to reside elsewhere on the protein.
In future work, the collaborators will investigate whether this protective function resides with FAD or whether FAD was retained in the evolutionary process solely for its ability to stabilize the AidB tetramer.
This work was supported by National Institutes of Health Grants R01-GM072663 (to Sean Elliott) and P30-ES002109 (to Catherine Drennan) and National Science Foundation Grant MCB-0543833 (Drennan). Professor Drennan is a Howard Hughes Medical Institute Investigator.
The paper is available at http://pubs.acs.org/doi/full/10.1021/bi201340t, or click on the image below.
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).