Professor Whitty was awarded a 4 Year grant by the National Institute of Health (NIH) to further his studies of NF-kB Modulators. The title of the Research Project is: Structure and Mechanism of NF-kB Essential Modulator (NEMO).
This funding will allow Professor Whitty and his Co-PIs Professors Karen Allen of Chemistry and Thomas Gilmore of Biology to advance our understanding of the signaling scaffold protein NF-κB essential modulator (NEMO), a component of the inhibitor of κB kinase (IKK) complex, which is a key regulatory node for NF-κB signaling. In addition to NEMO playing a role in the chronic hyperactivity of NF-κB in human diseases, mutations in NEMO are found in several human immunodeficiency diseases. The long-term goals of the project are to understand how scaffolding proteins such as NEMO use conformational change to regulate the functional interactions between the signaling proteins that are bound to them, to elucidate the structural basis for disease-causing mutations in key regions of NEMO, and to identify new target sites for small molecule drugs that modulate NEMO activity.
Congratulations to Professors Whitty, Allen and Gilmore and their research team!
The Department of Chemistry and Chemical Instrumentation Center (CIC) was recently awarded a National Institute of Health Shared Instrumentation Grant (NIH SIG) led by Dr. Norman Lee, Director of CIC, to acquire a MicroScale Thermophoresis (MST) instrument. This instrument will enable investigators in Chemistry, Biology, Biochemistry and others to advance their research in life processes and allow their investigations to move into new areas that would enrich student and postdoctoral training. The instrument’s capabilities will also enhance active research projects involving protein-protein and protein-ligand interactions as well as protein conformation changes. The new MST instrument will enhance our biophysical capability at BU to meet the current and evolving research needs of the faculty and students.
Congratulations and a special thank you to Dr. Lee and all faculty who participated on the Departmental grant for their efforts on getting this new MicroScale Thermophoresis instrument!
Dr. Sean Elliott Receives 4 Year National Institute of Health Grant to study “Structure, Function and Diversity in the Bacterial Cytochrome c Peroxidase Family”
The new grant will enable studies in the Elliott Group to dissect the way in which nature has made use of a common motif of bioinorganic chemistry, the iron-bearing structure known as a c-type heme, and to utilize it for diverse chemistry. While Elliott has a long-running interest in heme and redox chemistry, here the group studies the titular ‘bacterial cytochrome c peroxidase’ (or, bCCP) family of enzymes. While prototypical bCCPs are found in gram negative microorganisms where they detoxify endogenous or exogenous hydrogen peroxide (H2O2), the Elliott group has realized that there exist in microbes novel bCCPs which engage in unknown chemistry. In the work sponsored by the NIH, the Elliott group will use a combination of biochemistry, electrochemistry, spectroscopy and structural biology to elucidate the bCCPs found in under appreciated microbes, and attempt to rationalize why the enzymes work as they do.
The work to be supported is a team effort where the enzymes discovered and produced in the Elliott Group will be examined here at BU, but also in collaboration with structural biologists at MIT and spectroscopists at Carnegie Mellon and the University of Michigan.
As bCCPs are enzymes on the front-line of the native defenses of NIH Select List pathogens including Pseudomonas aeruginosa, Burkholderia complex species, Vibrio cholerae, Campylobacter jejuni, and Yersinia pestis, these studies will provide fundamental insight into the long-term development of new antimicrobial compounds that will target the novel features of bCCP structure.”
Dr. Elliott, who is also a two time recipient of the Scialog® Award Research Corporation (2010-2011), and received the 2007 Gitner Award for Distinguished Teaching in 2007 and an NSF CAREER Award in 2005 (among other honors), works with the Elliott Research Group to investigate the interplay between biological systems and redox-active species (e.g., metal ions, organic radicals, disulfide bonds, reactive oxygen species). Their emphasis is on the kinetic and thermodynamic basis for catalytic redox chemistry, as well as the molecular basis of how nature tune redox cofactors do the hard work of Life.
Dr. Arturo Vegas was recently featured in BU Today for his research into Type 1 Diabetes. The full article is called “New Targets to Treat Type 1 Diabetes” and there’s an excerpt from the article by Barbara Moran is below.
“Type 1 diabetes is rare but devastating. A person’s own immune system attacks the pancreas, destroying insulin-producing tissue and the body’s ability to regulate blood sugar. About five percent of people with diabetes—approximately 1.25 million Americans—have this form of the disease, according to the American Diabetes Association. Unregulated blood sugar can lead to blindness, kidney failure, and death.
Scientists aren’t sure what causes type 1 diabetes, though they suspect that a genetic predisposition, combined with an environmental trigger, causes a sudden disruption in the immune system that causes it to attack the body’s own tissue. The only treatment is a lifetime of careful blood sugar monitoring, with insulin injections as needed.
But what if there were a way to block the immune system before the damage was done, preserving at least some of the pancreas’ ability to produce insulin? That’s the goal of Arturo Vegas, a Boston University College of Arts & Sciences assistant professor of chemistry, whose lab combines biology, chemistry, materials science, and engineering to develop targeted therapies for complex diseases like diabetes. He recently was awarded a prestigious $1.4 million Type 1 Diabetes Pathfinder Award from the National Institutes of Health (NIH) to pursue the work.”
Congratulations Dr. Vegas!
Dr. Arturo Vegas was awarded 5 years of research support from the National Institute of Health through the New Innovator Award for his proposal entitled “Targeted Immunomodulation of the Diabetic Islet Microenvironment.”
His interest in the project springs for the fact there are currently no effective treatments for the autoimmunity that causes type 1 diabetes. Generalized immunosuppressive therapies are impractical for long-term care, and there remains a critical need to develop targeted therapies to treat diabetes-causing autoimmunity. To address this important challenge to the treatment of type 1 diabetes, this research focuses on the development of novel islet-targeted conjugates, nanomaterials, and targeting ligands to localize immunosuppressive agents to the islet microenvironment and enable drug release upon the onset of islet inflammation.
Professor Sean J. Elliott was recently awarded 4 Years of funding from the National Institute of Health for his proposal entitled: Redox Reactions of the AdoMet Radical Enzyme Superfamily.
The new grant will fund research into the oxidation/reduction chemistry of enzymes that belong to the AdoMet Radical Enzyme (ARE) superfamily. The ARE superfamily makes use of an unusual iron-sulfur cluster and S-adenosyl methionine to achieve a diverse array of chemical transformations. This research is relevant to human health, as AREs are important enzymes in the production of natural products that can serve as drug molecules. The project will provide insights into the fundamental processes of ARE function , and provide a new view in how similar enzymes achieve diverse chemistry.
Congratulations to Professor Elliott and his group on earning this award. For more information about Dr. Elliott and his research please visit his faculty page.
The Chemistry Department is one of the most active research departments at Boston University. With 24 research active faculty involved in many different focus areas, we are committed to a research active learning environment where our faculty and students are afforded the opportunity to do cutting edge chemical research. In order to continue to build on our strong research focus, our faculty have submitted over 30 grant proposals during the 2015-2016 academic year, with 20 of them being awarded totaling over $5 million in new funding this year alone.
Below is a list of the awarded grant proposals as well as their abstracts. For more information about the Faculty member who will the the Principal Investigator please click on their name.
Boston University Chemistry Department Awarded Grants Academic Year 2015-2016
Scott Schaus, National Institute of Health / National Institute of General Medical Science
Enantioselective Catalytic Boronate Reactions
The development of new chemical methodologies is an important objective of organic synthesis. An area that continues to inspire chemists is the chemistry of organoboranes and boronates. The unique properties of boron and the ability to activate organic boronates to deliver carbon nucleophiles has yielded an impressive array of chemical methods and processes. We will extend the ability of organoboranes and boronates to deliver carbanion equivalents in novel condensation reactions including chemoselective carbonyl condensations and multicomponent reactions. The reactions will be rendered asymmetric through the development of asymmetric catalysts and chiral boronate reagents and the utility of the methods developed demonstrated by the asymmetric synthesis of pharmaceuticals and natural products. Significant advances have been made in the mechanistic understanding of boronate activation via ligand exchange with chiral diols. We will use the mechanistic insight we have obtained to expand the repertoire of reactions catalyzed by dynamic ligand exchange processes to include acyl cyanides as electrophiles, borono-Petasis reactions, and ortho-quinone methide chemistry. Our continued interest in reaction discovery has led to the identification of chiral diol acid catalysts capable of promoting the enantioselective addition reactions to acetals. We seek to explore this reactivity and expand it to include types of functionalized nucleophiles in additions to oxoniums and iminiums and boronate hetero-Diels–Alder reactions. Goals of the research program include developing a breadth of reactivity, providing access to novel chiral blocks, and new reaction development. Bond constructions are selected to access chiral synthetic intermediates that could be used in the construction of pharmaceuticals and natural products. The results will transform the way boronate nucleophiles are utilized in enantioselective synthesis.
John Straub, National Institute of Health
Probing the role of membrane and cholesterol on APP-C99 structure and dynamics
Aggregation of proteins of known sequence is linked to a variety of neurodegenerative disorders. Familial mutations in the Amyloid Precursor Protein (APP), from which the amyloid β (Aβ) protein associated with Alzheimer’s Disease (AD) is derived, have been linked with the early onset of amyloid disease.
With this computational and theoretical research grant, augmented by synergistic experimental research collaborations, we will determine the structure and dynamics of the 99 amino acid transmembrane fragment of APP (APP-C99) in membrane environments in order to address fundamental biophysical questions articulated in three Specific Aims. (1) We will explore how length, sequence, and membrane composition influence the structure of the APP-C99 monomer. (2) The structures of APP-C99 dimers and the associated stability as well as the monomer-dimer equilibrium are also influenced by membrane composition and C99 sequence. We will investigate the influence of these environmental factors on the structure and dynamics of dimer formation. (3) We will also determine how APP-C99 interacts with cholesterol and cholesterol-analogs, as well as how those interactions influence APP-C99 structure and dimerization.
Plasmonically Enhanced Stimulated Coherent Spectroscopy
There is growing interest in using plasmonics to enhance and control chemistry on surfaces for applications such as chemical catalysis, pollution mitigation and energy conversion. The proposed time-domain experiments are aimed at developing a better dynamical and structural description of how molecules interact with plasmonic materials. Differences in energy fluctuation timescales, interaction strengths and energy distributions are anticipated for molecules on plasmonic surfaces as compared to molecules in liquid solutions. Characterizations of these properties are central to understanding chemical activity occurring on these substrates. Plasmonically enhanced stimulated coherent vibrational and electronic spectroscopic measurements of analytes on plasmonic substrates will be obtained to learn about these interactions. Fabricated metal nanoparticle cluster arrays will be employed here. This substrate type provides a wide range of design parameters that will be used to maximize signal strengths and robustness for the planned studies. The proposed research effort will be carried out by two Boston University PIs with complementary expertise in ultrafast spectroscopy and nanoscience.
Tom Tullius, National Science Foundation
Chemical probing of RNA tertiary structure in a whole transcriptome at single‐atom resolution
RNA (ribonucleic acid) is now widely appreciated to be a key participant in nearly all of the activities of the cell, yet we have limited information on the three-dimensional structures of most RNA molecules. This presents a challenge, because we know that the biological function of an RNA molecule depends on its structure. To understand the relationship between structure and function for the large number of RNA molecules that populate the cell, new high-throughput experimental approaches for structure determination are needed. The aim of this project is to develop a new experimental method that can provide detailed information on the three-dimensional folding of all the RNA molecules in a cell, in one experiment. The new method combines chemical probing of RNA structure by the hydroxyl radical, the quintessential Reactive Oxygen Species, with analysis by high-throughput sequencing, so that the structures of all RNA molecules in a cell can be monitored simultaneously.
John Porco, National Institute of General Medical Science
Chemical Synthesis of Complex Natural Products for Translational Science
The National Institutes of Health, Institute of General Medical Sciences (NIGMS), has awarded Professor John Porco and coworkers (http://sites.bu.edu/porcogrp/) a five year MIRA (R35) grant entitled “Chemical Synthesis of Complex Natural Products for Translational Science.” The Maximizing Investigators’ Research Award (MIRA-R35), an Outstanding Investigator Award, is a grant that provides support for all of the research in an investigator’s laboratory that falls within the mission of NIGMS. Within these bounds, investigators have the freedom to explore new avenues of inquiry that arise during the course of their research. The goals of the MIRA (R35) research program are to continue chemical syntheses of bioactive molecules and expand efforts and capabilities in translational science. The MIRA effort effectively replaces two previous NIGMS-funded RO1 grants (Biomimetic Synthesis of Complex Natural Products (GM-073855) and Chemical Synthesis of Bioactive Flavonoid and Xanthone-Derived Natural Products (GM-099920) which were highly productive and led to 41 publications from 2010 – 2015. As part of the MIRA project, the Porco group will continue development of novel synthetic methodologies for concise entry to bioactive classes of natural products including oxaphenalenones, meroterpenoids, polyprenylated acylphloroglucinols, tetrahydroxanthones, and dimeric chromones. The project will also continue major emphasis on collaborations to study biological properties and mode of action (MoA) of target molecules for ultimate use as pharmacological therapies for human cancers as well as viral and bacterial illnesses.
Malika Jefferies-EL, National Science Foundation
Early Career Investigator Workshop
In an effort to develop the next generation of Chemistry researchers, the National Science Foundation Division of Chemistry has sponsored the proposal of Professor Malika Jeffries-EL and co-PI Jeff Moore for the University of Illinois-Urbana Champagne to hold an NSF Chemistry Early Career Investigator Workshop. The objective of these workshops is to provide early career chemist with networking opportunities and relevant information needed to better assess their research ideas, projects, and plans so as to more effectively compete for grant applications to the NSF CAREER program, other NSF programs and other federal agencies. The workshop was held March 10th-11th 2016 in Arlington VA at the Hilton Garden Inn, which is close to the NSF headquarters, enabling the participation of many program officers. The workshop is had approximately 120 participants and will be open to investigators performing research in NSF-supported disciplines within the United States. While the workshop is primarily intended for junior faculty members, advanced graduate students, postdocs, and other research scientist.
Ksenia Bravaya, Boston University
Patrick Mclellan Leavitt Research Award
This award is designed “to support research of one or more non-tenured junior faculty members, or graduate students, in chemistry or biology at the College of Arts and Sciences. Preference shall be given to female faculty who demonstrate a commitment to encouraging women to study science, or to female graduate students.”
Dr. Bravaya will use these funds to support her research into challenging electronic structure phenomena in biomolecules and systems relevant for materials, which include photoinduced processes, autoionizing electronic states, and magnetic field effects. This award will help her and her team use and develop high-level electronic structure methods targeting processes involving multiple electronic states, chemistry of open-shell species in magnetic fields, and electronically excited and metastable systems.
Mark Grinstaff, National Science Foundation
SusChEM: Glycerol Polycarbonates as New Biomaterials
The future development of medical devices. Scientific advances, such as those described in this NSF sponsored research, will support US industries, which play an important role in this medical polymers market estimated to exceed $3.5 billion by 2018. This grant support undergraduate students and graduate students, who will benefit from an interdisciplinary cutting-edge research and educational experience that encompasses training in biomaterials and polymer chemistry. Students will be encouraged to think independently and creatively while recognizing the importance of collaborating with other experts (e.g., materials scientists, pathologist, biomedical engineers, and patent lawyers). These activities will contribute to positive societal outcomes by fostering excitement for basic research while educating and training a future workforce.
In the biomaterials and biomedical field, degradable polymers such as poly(lactic acid) and poly(glycolic acid) are widely studied and are an integral component of many medical device products. Although extensively used, these poly(hydroxy acid)s possess a number of limitations including: 1) limited capability for backbone functionalization; 2) acidic products upon degradation; and 3) poor control over molecular weight and dispersity. Consequently, there is significant need for new polymeric biomaterials that are amenable to facile modification, multiple processing or manufacturing methods, and controlled degradation without the generation of a local acidic environment. With NSF funding, the PI (Grinstaff) and his team will design, synthesize, and evaluate of a novel class of natural metabolite-based, non-toxic, and biodegradable polymeric materials based on a polycarbonate of glycerol. The activities in this highly interdisciplinary and cutting-edge research environment will also afford educated and trained undergraduate and graduate students for employment in industry and academia.
Mark Grinstaff, Samsung
Basic Research on New Ionic Liquid Electrolytes: Synthesis
This basic science research project directed by Professor Grinstaff investigates his interest in new ionic liquids as potential electrolytes for Li ion batteries. Given his interest and past publications, Samsung has reached out to sponsor this project. Specifically, the Grinstaff laboratory will synthesize a small library of 10 new phosphonium and piperdium ionic liquids. We will mix these ionic liquids with differing Li salts and characterize the thermal properties, viscosity, conductivity, and electrochemical window of these electrolyte compositions.
Mark Grinstaff, MIT/Comm. Of Mass
Translation of a Hydrophilic Coating for Latex Condoms: The HydroGlide Coating
The HydroGlide Coating is a novel and stable hydrophilic coating on latex condoms that can maintain its lubricity when in contact with water. This technology will promote consistent and proper condom usage, while improving user satisfaction. The goal is to translate this novel latex coating technology to the market through collaboration with Biocoat Incorporated who will optimize this coating prototype towards one that is adaptable towards large-scale manufacturing under GMP.
Bjoern Reinhard, Millipore
Plasmonic Nanofilters For Viral trapping and inactivation
This award will go towards research into creating plasmonic metamaterials to develop a novel class of photonic filters that are capable of selectively trapping and inactivation of viruses. Several complementary technology developments, ranging from state-of-the-art electron-beam lithography, fabrication methods combined with simulation and design will be aimed at developing 21st century adaptive filters for biopharmaceutical applications. Evaluation of the Optical gradient forces in fabricated membranes will be combined with multi-physics modeling that include both plasmonics and hydrodynamics. Experiments on fluid feed materials and virus systems selected by EMD will be performed to characterize selective trapping. Data will be shared openly between BU and EMD, under NDA. An assessment of manufacturability, scalability will be performed in close consultation with engineers and scientists at EMD.
Bjoern Reinhard, BMC Corp.
Nanoplasmonic Metamaterial Filters
This project explores the mechanism underlying virus inactivation through laser irradiation.
Bjoern Reinhard, National Cancer Institute
Illuminating Dynamic Receptor Clustering in the Epidermal Growth Factor Receptor
Dysregulation of members of the epidermal growth factor (EGF) receptor (EGFR) family is associated with oncogenesis and tumor growth. Due to its relevance in cancer development, EGFR is an important target in cancer drug discovery, and several EGFR targeted therapies have already been developed. Their clinical success has, however, often been modest, reinforcing the need for a more complete understanding of the EGFR signaling pathway. This proposal focuses on the insufficiently understood role of large-scale EGFR associates (“clusters”) in signaling initiation and transduction, in particular. While it has long been known that ligand induced dimerization plays a critical role in receptor signaling, there is growing evidence that this textbook model needs to be augmented to account for the heterogenous lateral distribution of the receptor in the plasma membrane. The local enrichment of the receptors in ”micro-domains” or ”nanoclusters” could strongly affect cooperative receptor interactions and shift the local EGFR association equilibria through a local concentration effect. The experimental investigation of the fundamental mechanisms underlying the large-scale receptor organization with conventional fluorescence microscopy remains challenging, due to the method’s limitation with regard to throughput, spatial and temporal resolution, and maximum observation time. Plasmon Coupling Microscopy (PCM) is a novel non-fluorescence based approach that uses electromagnetic interactions between noble metal nanoparticles (NPs) to investigate receptor clustering on subdiffraction limit distances (but beyond the spatial barrier o Fluorescence Resonance Energy Transfer, FRET). NP’s do not blink or bleach, are very bright, and can be imaged in a conventional widefield microscope. Consequently, PCM facilitates the monitoring of EGFR clustering without limitations in observation time in many individual cells simultaneously. This competitive renewal builds upon the plasmon coupling based tools developed in the previous funding cycle and outlines a vigorous research plan to elucidate the structural origin of dynamic EGFR clustering. PCM will then be applied to test the hypothesis that receptor clustering regulates the mode and strength of signaling and to elucidate the mechanisms underlying a spatial regulation of signaling intensity and outcome. The obtained insight will improve the understanding of spatial regulation mechanisms for a broad range of receptors. Noble metal NPs are not only superb optical labels for characterizing EGFR clustering in the plasma membrane, but they also represent potential therapeutic tools to restore and enhance negative EGFR signaling after covalent attachment to EGF. This hypothesis is experimentally tested in this proposal. If successful, this strategy would provide a new approach for overcoming apoptosis evasion in cancer.
Research For Undergraduates Program: Chemistry Research Addressing Biological Problems
This REU site will afford 30 undergraduates (10 per summer) the opportunity to engage in cutting edge, basic chemical research projects that address biological problems. REU students can choose from among 24 groups in BU’s Departments of Chemistry, Biology, or Biomedical Engineering. They will work in newly renovated laboratories, have access to the synthetic and computational resources of BU’s leading research centers, and be trained on state-of-the art instrumentation. The goal of the program is to provide undergraduates from 4-year colleges and community colleges who have limited or no research opportunities at their home institutions with an intensive, interdisciplinary research experience. At least 50% of the participants will be from community colleges with no research opportunities at their home campuses. The demographic aim is to have at least 70% of the students to be underrepresented minorities and at least 50% to be women. The program will also give preference to veterans applying from the target institutions. By fully integrating the REU students into the daily life of the laboratories and through mentoring by faculty, graduate students, and postdoctoral research associates, the REU students will fully experience the breadth of chemistry research and be motivated to pursue careers in science.
Mark Grinstaff, L-Oreal
Poly-amido-saccharide (PAS) Biomaterials for Cosmetic and Beauty Applications
This project will explore a new class of polysaccharides, recently reported, for their properties as new materials as well as their biological activity in anti-ageing and/or preservatives and/or photoprotection and/or depigmentation.
Aaron Beeler, National Science Foundation CAREER
Chemical Transformations Enabled by Flow Chemistry
This award funds specific projects that are integral to the long term development of the Beeler Research Group. The overarching objective of our research is synthesis of small molecules that are used as tools to study human diseases. To achieve these goals we have identified a number of reactions that are highly enabled by flow chemistry. The scientific projects outlined in this proposal will result in sigfnificant advances toward the synthesis of a number of important biologically active molecules. Furthermore, the projects will provide advancements in flow chemistry that will enable chemists in acadmia and industry to implement a number of challenging reactions. The education projects in the proposal will provide training for undergraduates in flow chemistry, which is emerging as a critical technology in industry. The outreach projects will provide high school students from a wide range of socioeconomic backgrounds with a foundational path toward STEM higher education and careers. The first Aim is focused on expanding the utility of our flow photochemistry platform to develop reactions that will be highly useful in synthesis and medicinal chemistry. The second Aim is to develop a platform that is capable of milligram to multigram scale electrochemical reactions in flow. The third Aim will utilize highly reactive diazoalkanes in a Buchner reaction to access complex scaffolds. The proposal also outlines our continued involvement in outreach and education, including the Upward Bound program at Boston University to educate local high school students in chemistry, developing a summer camp for high school students, and integrating flow chemistry into the undergraduate laboratory curriculum.
Debbie Perlstein, National Science Foundation CAREER
Elucidating the role of ATP in cytosolic iron sulfur cluster biogenesis
Dr. Perlstein’s research focuses on how metals are mobilized and monitored within the cell so that they get to where they need to go and do not end up in places they shouldn’t. With this new five-year grant, Dr. Perlstein plans to unravel the molecular mechanism by which iron-sulfur cluster cofactors are assembled in the cytosol of eukaryotic organisms. Since inhibition of this first step in cluster biosynthesis can lead to defects in DNA replication, DNA repair and protein synthesis, she expects this work will provide new insight into how cluster biogenesis affects these other fundamental biochemical pathways.
With the CAREER award, Perlstein also plans to develop new undergraduate course curriculum as well as building on current STEM outreach program efforts to begin training the next generation of scientists.
Mark Grinstaff, Brigham & Women’s
Efficacy and Safety of a Novel, Implantable Drug-Eluting Film in Sarcoma
Despite aggressive multimodality therapies combining surgery, radiation, and/or chemotherapy, mesothelioma is essentially a universally fatal cancer with the majority of patients succumbing to local recurrence. To date, there is no effective cure for this disease or means to prevent recurrence. Consequently, new approaches, biomaterials, and mechanisms to deliver pharmacologically active agents are needed. In the current proposal, we utilize a murine model of human mesothelioma to investigate a new approach to reduce intracavitary tumor recurrence with the delivery of chemotherapy via unique tumor localizing polymeric nanoparticles (NPs) administrated locally at the time of surgical resection. The particle localizes to tumor in situ where upon endocytosis these “expansile” nanoparticles (eNPs) undergo a pH dependent transformation and swell from 100 nm to 1000 nm in diameter thus releasing the encapsulated chemotherapeutic agent intracellularly and acting as a drug depot, or reservoir, to deliver high local drug concentrations. Uniquely, expansion of eNPs also results in a functional depot whereby subsequently delivered intracavitary chemotherapy is concentrated inside eNP with prolonged delivery in situ at the sites of tumor where eNP accumulate. This is in contrast to conventional polymer delivery systems that degrade (e.g., poly(lactic-co-glycolic acid) particles), and result in burst release of their drug payload. We hypothesize that these eNPs will, via this unique mechanism, afford a higher intracellular concentration of paclitaxel (Pax), with greater efficacy in the prevention of local recurrence of mesothelioma after surgery that is superior to standard resection or Pax alone without adversely affecting healing at the surgical site. Importantly, we have data demonstrating that eNPs are readily internalized by cancer cells, act as a drug depot, and are superior to the standard Pax-Cremaphor formulation in preventing microscopic malignant disease in vivo.
Mark Grinstaff, NIH
Dissolvable Hydrogel Dressing for the Treatment of Burns
This will study the synthesis, characterization, and evaluation of a hydrogel dressing that dissolves and can be easily removed from the wound surface of a patient with second degree burns with no further trauma. Burns are one of the most common and devastating forms of trauma. Each year, more than 300,000 people die from fire-related burn injuries and millions suffer from burn-related disabilities and disfigurements with psychological, social, and economic effects on both the survivors and their families. Dressing removal is reported to be the time of most pain (after the burn itself) and opioids continue to be the mainstay of treatment for the burn patient. The duration of a burn dressing change in a typical injury requiring ICU/OR level care is often at least 60 minutes with induction of general anesthesia, which can extend to more than three hours depending on the case. At present, all clinically approved available dressings adhere to the wound surface so that each change of dressing leads to traumatization of newly formed tissues on the outer layer of the body’s surface, delayed healing, and great personal suffering for the injured patient. The proposal describes a thiol terminated dendron and a bifunctional NHS-activated PEG that react with each other to form a thiolester linked hydrogel dressing that can be subsequently dissolved by exposure of an aqueous thiol solution via a thiol-thiolester exchange mechanism. These experiments will test the hypothesis that a hydrogel-based, dissolvable burn dressing will provide a barrier to infection, promote wound healing, and be easily removable on demand. Importantly, it presents preliminary data demonstrating the synthesis, characterization, and performance of a dissolvable hydrogel dressing prototype.
Tuning directionality for CO2 reduction in the oxo-acid:ferredoxin superfamily
Exploiting catalytic chemistry for bioenergy production requires a detailed understanding of the molecular mechanisms of multi-electron redox processes, particularly those that transform/capture CO2. Understanding the molecular details of these complex reactions is a major challenge in modern energy science, particularly in the context of CO2 transformations, and the way in which bacteria and archaea capture CO2 for biomass. Here, we have focused on the remarkable catalysts used by nature to achieve either the oxidative liberation of CO2, or its formal reduction (and capture) in the form of useful intermediaries en route to biomass.
The enzymes that achieve CO2 reductions are highly powerful catalysts; yet very little is known about how they work, nor how they can be tuned to favor CO2 reduction chemistry. Through the completion of the project, this knowledge gap will be addressed in the context of the enzymatic chemistry of the oxo-acid:ferredoxin oxidoreductase (OFOR) superfamily, which is capable of CO2 reduction. We believe that our studies of the OFOR superfamily will reveal the molecular details of how nature biases the reactivity of an enzyme to preferentially reduce CO2. These efforts will yield foundational knowledge that will be broadly applicable to marrying the thermodynamics of redox reactions to atomistic information of enzymatic mechanism. We will examine a series of OFOR enzymes through three Aims over a 3-year period.
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).