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.
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).
This award will reinforce our Life Science research infrastructure on the Charles River Campus by renovating space on the 4th floor in the East Wing of the Metcalf Science and Engineering Center Department of Chemistry space. Started in April, 2010, the one-year effort will renovate 6,700 square feet of laboratory and office space to create four laboratory modules for state-of-the-art research in synthetic organic chemistry and supporting laboratory space for analytical chemistry. The flexible laboratory layout will enable technology-facilitated medicinal chemistry. Complementary faculty and meeting space will be developed to fully support real and virtual conferencing that facilitates engagement and collaboration among research scientists on the Charles River and Medical campuses as well as sites outside of BU. These renovations of four research laboratories will provide the infrastructure for the chemical sciences to realize BU’s biomedical research vision, which has been constrained by outdated and inflexible infrastructure available in the Metcalf Center for Science and Engineering (renovated in 1983). It will bolster BU’s leadership position in translational science by providing a robust environment for multidisciplinary research efforts bridging chemistry and biology. This NIH facilities renovation award is the first federally funded renovation grant on the Charles River Campus in BU’s history.
NIH funds Pinghua Liu and his group to perform mechanistic studies of enzymes in isoprenoid biosynthesis
The goal of this award ($1.9 million over 5 years – 2010-2015) is to characterize the mechanism of a key enzyme in the deoyxylulose biosynthetic pathway as well as identify its key partner proteins. This pathway, identified only in bacteria and plants, produces the required compounds for isoprenoid synthesis. The results of this work could eventually lead to new broad-spectrum antibiotics or toward more efficient bioengineering based isoprenoid production. The work has developed an enzyme preparation that is many times more active than those previously reported, providing a crucial piece to illuminating enzymes. These isoprenoid biosynthetic studies will guide the development of mechanism- based inhibitors of the DXP pathway enzymes, which can be used as broad-spectrum antibiotics. The public health benefit will result from the development of effective new treatments for drug-resistant strains of pathogens (e.g., tuberculosis), currently of increasing concern worldwide.
The National Institute of General Medical Sciences (NIGMS) is continuing its support of the CMLD-BU as one of five Centers of Excellence addressing the problem of how to develop small molecule libraries and techniques for making them that meet all the needs of pharmaceutical and biomedical scientists.
The CMLD-BU was originally established in 2002. The renewal is for another 5 years (through 2013) and is worth more than $11.5 million. The first year’s funding, $2.6 million, will be used to develop microfluidics and other strategies to synthesize small molecules for application by the biological community. The program is highly collaborative. Professor John A. Porco, Jr., who is the Director and Principal Investigator, is joined by Co-PI’s Professors Jim Panek, Scott Schaus, John Snyder, and Corey Stephenson, who are leaders in the field of organic chemistry.
The goal of the Center is to develop cutting-edge technologies to generate, analyze, and optimize chemical libraries and synthesize thousands of novel chemical entities using high-throughput techniques. It is also making these methods and libraries broadly available for biomedical research and drug discovery. The CMLD’s PI’s are collaborating with biologist, Professor Tom Gilmore, to determine the physiological activities of new molecules.
Sean Elliott receives 5-year Early Faculty Development (CAREER) Award from the National Science FoundationFrom BU Today:
The National Science Foundation honored CAS assistant professor of chemistry Sean Elliott for his research on biological electron transfer, with the Faculty Early Career Development (CAREER) Award, a five year grant that will give Elliott the opportunity to further develop a course curriculum that highlights the intersection of chemistry and biology.
CAREER awards are presented by the NSF to teacher-scholars who are “most likely to become the academic leaders of the 21st century,” according to a release. “Awardees are selected on the basis of creative plans that effectively integrate research and education within the context o fthe mission of their organization.”
Elliott’s work in biological electron transfer examines how organisms convert chemicals into useful energy. The grant will also support Elliott’s study about series of cytochromes, iron-containing proteins. “This is very exciting news,” says Elliott, who joined Boston University faculty in 2002. Elliott majored in Chemistry and English at Amherst College, and completed his Ph.D. in chemistry at Caltech in 2000. He has also done post-doctoral work at the University of Oxford. “In particular, I’m most proud as it reflects the success of my graduate and undergraduate students in the lab as well as in the classroom.”