Chemical Biology Discussion Group Year-End Symposium

Chemical Biology Discussion Group Year-End Symposium

Monday, May 18, 2015

The New York Academy of Sciences

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Chemical biology is a diverse and dynamic field involving chemical approaches to studying and manipulating biological systems. The goal of the Academy's Chemical Biology Discussion Group meetings is to enhance interactions among local-area laboratories working in chemical biology and to feature forefront research in chemical biology to the wider community. The meeting traditionally covers a range of current topics in chemical biology, including chemical probe development, organic synthesis, biosynthesis, protein engineering, nanotechnology, and drug discovery. The annual year-end meeting features distinguished keynote speaker Scott J. Miller of Yale University. This will be followed by shorter, cutting-edge talks by graduate students and postdoctoral fellows selected from participating tristate-area institutions, and a poster session.

This event will also be broadcast as a webinar.

Please note: Transmission of presentations via the webinar is subject to individual consent by the speakers. Therefore, we cannot guarantee that every speaker's presentation will be broadcast in full via the webinar. To access all speakers' presentations in full, we invite you to attend the live event in New York City when possible.

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The Chemical Biology Discussion Group is proudly supported by   American Chemical Society


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Speakers

Organizers

David M. Chenoweth, PhD

University of Pennsylvania

David M. Chenoweth was born in Indiana and received his B.S. degree from Indiana University-Purdue University Indianapolis (IUPUI) in 1999. During his time at IUPUI, he performed undergraduate research in the labs of David Nurok. After graduation, he completed an internship in organic chemistry at Dow AgroSciences prior to joining the Discovery Chemistry Research Department at Eli Lilly in 2000, where he worked with Thomas Britton. David moved to Caltech in 2003 to pursue a Ph.D. degree in the labs of Peter B. Dervan. After receiving his Ph.D. from Caltech in 2009, he was an NIH Postdoctoral Fellow at MIT with Timothy Swager. David was appointed as an Assistant Professor in the Department of Chemistry at the University of Pennsylvania in 2011. He is also a member of the Biochemistry and Molecular Biophysics Graduate Group in the Perelman School of Medicine and the Bioengineering Graduate Group in the School of Engineering and Applied Science at the University of Pennsylvania.

E. James Petersson, PhD

University of Pennsylvania

E. James Petersson was educated at Dartmouth College, where he worked in the laboratory of David Lemal. He then studied under Dennis Dougherty at the California Institute of Technology as an NIH Predoctoral Fellow. After obtaining his Ph.D. in 2005, he worked as an NIH Postdoctoral Fellow at Yale University with Alanna Schepartz. He was appointed as Assistant Professor in the Department of Chemistry at the University of Pennsylvania in 2008 and in the Biochemistry and Molecular Biophysics group in the Perelman School of Medicine in 2013. His laboratory designs methods for labeling proteins using synthetic amino acids and for using those labeled proteins to understand protein folding and protein misfolding diseases. For this work, he has been the recipient of several awards, including a Sloan Fellowship, an NSF CAREER award, the JPOC Early Excellence in Physical Organic Chemistry award, and recognition as a Searle Scholar.

Sonya Dougal, PhD

The New York Academy of Sciences

Keynote Speaker

Scott J. Miller, PhD

Yale University

Scott J. Miller was born on December 11, 1966 in Buffalo, NY. He received his BA (1989), MA (1989), and PhD (1994) from Harvard University, where he worked in the laboratories of Professor David Evans as a National Science Foundation Predoctoral Fellow. Subsequently, he traveled to the California Institute of Technology where he was a National Science Foundation Postdoctoral Fellow in the laboratory of Robert Grubbs until 1996. For the following decade, he was a member of the faculty at Boston College, until joining the faculty at Yale University in 2006. In 2008, he was appointed as the Irénée duPont Professor of Chemistry, and in 2009, the Chairperson of the Chemistry Department. Professor Miller's research program focuses on problems in catalysis. His group employs strategies that include catalyst design, the development of combinatorial techniques for catalyst screening, and the application of these approaches to the preparation of biologically active agents. Two particular interests of his laboratory are (a) the selective functionalization of complex molecules, and (b) the exploration of potential analogies between synthetic catalysts and enzymes.

Short Talk Presenters

Madalee Gassaway, MPhil

Columbia University

Madalee Gassaway Wulf grew up in Santa Cruz, California and earned her BS in Chemistry with a minor in Music from the University of California, Berkeley in 2011. During her time at UC Berkeley, she had the privilege of studying under Ming Hammond, where she worked towards the synthesis of unnatural amino acid and cyclic nucleotide ligands for mutated riboswitches. Upon graduation, Madalee joined Dalibor Sames’ group at Columbia University in 2011. Her research focuses on opioid receptor, receptor tyrosine kinase (RTK), and neurotrophic factor signaling in the brain and their roles in neural plasticity with the ultimate goal of developing new therapeutics for neuropsychiatric disorders. Madalee’s efforts center around both the design and synthesis of small molecule modulators for these receptors, as well as understanding the biology behind their mechanisms of action.

Ching-Wen Hou

University of Delaware

Ching-Wen Hou is a current Ph.D. candidate in chemistry and biochemistry in the lab of Prof. Catherine L. Grimes at the University of Delaware. She received her Masters in Biopharmaceutical Science under the direction of Prof. Wey-Jinq Lin at the National Yang Ming University in Taiwan. She continued working in this lab as a research assistant for a few years before moving to the University of Delaware. Her current work focuses on understanding the interaction of our innate immune system with bacteria. Her future plans include relating basic research to translational medicine in the pharmaceutical industry field.

Brittany Riggle

University of Pennsylvania

Brittany Riggle is a sixth year PhD student in the Chemistry program at the University of Pennsylvania in the laboratory of Dr. Ivan Dmochowski. Her thesis work in bio-organic chemistry and chemical biology focuses on designing targeted xenon-129 contrast agents of use in magnetic resonance imaging and spectroscopy. She received her bachelors of science in chemistry with a specialization in biochemistry from the University of Virginia where she worked on microfluidic devices in the laboratory of Dr. James Landers.

Kelsey Schramma

Princeton University

Kelsey Schramma, a native of Colorado, received her B.A. in Chemistry from Mount Holyoke College in 2012. Working under Professor Megan Núñez, she attempted to convert the predatory bacteria Bdellovibrio bacteriovorus into host-independent organisms in the presence of Micrococcus luteus. Additionally, Kelsey performed research in the lab of Professor Christoph Schneider at the University of Leipzig and helped increase the substrate scope on the vinylogous Mannich reaction in 2011. She currently is a third year graduate student in the Department of Chemistry at Princeton University working with Professor Mohammad Seyedsayamdost.  Her research focuses on characterizing and elucidating the mechanism of radical S-adenosylmethionine dependent enzymes in the biosynthesis of natural products with unusual structural features.

Chamara Senevirathne, PhD

Memorial Sloan-Kettering Cancer Center

Chamara Senevirathne is a young bioorganic chemist from Sri Lanka. In 2003, he entered University of Peradeniya and earned his Bachelor degree majoring Chemistry with First Class Honors in 2007. After finishing the undergraduate program, he moved to the USA in 2008 to pursue his doctoral degree. He obtained his Ph.D. in Chemistry from Wayne State University, Detroit, Michigan in 2013 under the supervision of Prof. Mary Kay Pflum. His graduate work has focused on characterizing kinase cosubstrate promiscuity and developing an enzymatic tool to study phosphoproteomics using γ-phosphate modified ATP analogs. During his Ph.D. career, he published several research articles. He has been recognized as the most outstanding researcher in organic chemistry division at Wayne State University by awarding the Norman A. LeBel Endowed Graduate Award in Organic Chemistry, in 2010 and James C. French Graduate Award in Organic Chemistry, in 2012. Currently, he is working as a postdoctoral research fellow in Prof. Minkui Luo’s research group at Memorial Sloan-Kettering Cancer Center, New York, where he is modifying the Bioorthogonal Profiling of Protein Methyltransferase (BPPM) method to improve the technology for profiling the targets of protein methyltransferases.

Ting Wang, PhD

Albert Einstein College of Medicine

Dr. Ting Wang graduated from the Pharmaceutical Chemistry Department at Peking University. Since graduating, she has been working with Prof. Thomas Leyh at the Albert Einstein College of Medicine to elucidate the biology and molecular bases of function of the human cytosolic sulfotransferases, a disease-relevant enzyme family.

Sponsors

For sponsorship opportunities please contact Perri Wisotsky at pwisotsky@nyas.org or 212.298.8642.

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New England Biolabs

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Seton Hall University

Tri-Institutional PhD Program in Chemical Biology


The Chemical Biology Discussion Group is proudly supported by   American Chemical Society

Mission Partner support for the Frontiers of Science program provided by   Pfizer

Abstracts

Molecular Target Identification and Proposed Mechanistic Hypothesis for the Antidepressant and Neurorestorative Agent Tianeptine
Madalee M. Gassaway, MPhil1

The pharmacological treatments for depression and other related disorders available today continue to suffer from major problems, including low response rate, slow onset of therapeutic effects, loss of efficacy over time, and serious side effects. Consequently the need to discover new therapeutic approaches that address these disorders is urgent. Interestingly, the atypical antidepressant tianeptine already meets in part these clinical goals. Though three decades of basic and clinical investigations have characterized the physiological effects, the molecular target of tianeptine and its mechanism of action remain unsolved. Herein, we report the characterization of tianeptine as a μ-opioid receptor (MOR) agonist. Using radioligand binding and cell-based functional assays, including bioluminescence resonance energy transfer (BRET)-based assays for G-protein activation and cAMP accumulation, we identified tianeptine as an efficacious MOR agonist (Ki-Human of 383±183 nM and EC50-Human of 194±70 nM for G-protein activation). Tianeptine was also a full δ-opioid receptor (DOR) agonist, although with much lower potency (EC50-Human of 37.4±11.2 μM for G-protein activation). In contrast, tianeptine was inactive at the κ-opioid receptor (KOR). On the basis of these pharmacological data, we propose that activation of MOR (or dual activation of MOR and DOR) could be the initial molecular event responsible for triggering many of the known acute and chronic effects of this agent, including its antidepressant and anxiolytic actions through modulation of the glutamatergic system, making MOR a “new” player in the battle against depression.
 
Coauthors: Marie-Laure Rives, PhD2,3, Andrew C. Kruegel, MPhil1, Jonathan A. Javitch, MD, PhD2,3,4, and Dalibor Sames, PhD1
1 Columbia University Department of Chemistry, New York, New York, United States
2 Columbia University Department of Psychiatry, New York, New York, United States
3 New York State Psychiatric Institute Division of Molecular Therapeutics, New York, New York, United States
4 Columbia University Department of Pharmacology, New York, New York, United States

 

O-GlcNAcylation Stabilizes Nod2, an Innate Immune Receptor Involved in Crohn’s Disease
Ching-Wen Hou, MS1

Nucleotide-binding oligomerization domain2 (Nod2) is an intracellular receptor that can sense bacterial components, such as, Muramyl dipeptide (MDP). MDP is a peptidoglycan fragment from bacterial cell wall that can activate NF-kB, a transcriptional factor that induces the production of inflammatory molecules such as cytokines. In 2001, a genetic linkage analysis revealed three major mutations in Nod2 were linked to Crohn’s disease. Crohn’s-associated Nod2 variants have a loss of function phenotype where they display a decreased ability to turn on NF-kB. Recently, using the classic cycloheximide stabilization assay, we showed that Crohn’s-associated Nod2 variants have lower half-life compared with wild type Nod2 in cells. To further characterize this protein, the objective of this study is to determine if Nod2 is post translationally modified. GlcNAcylation is one of post translational modifications in which O-GlcNAc transferase (OGT) transfers N-acetylglucosamine (GlcNAc) from UDP-GlcNAc to selected serine and threonine residues of a target protein. As GlcNAc is a major component of peptidoglycan of bacterial cell wall and a large amount of GlcNAc is released from bacterial cell wall during cell wall remodeling, we hypothesized that Nod2 could be O-GlcNAcylated. Preliminary data show that wild type Nod2 and Nod2 variants are O-GlcNAcylated by using O-GlcNAc antibody (CTD110.6). In addition, increasing the O-GlcNAcylation level can increase the half- life of Nod2 in wild type Nod2 and affect Nod2 mediated NF-kB pathway .In future experiments, we will determine which residue of Nod2 is GlcNAcylated and investigate if this modification affects Nod2 mediated NF-kB pathway in Crohn’s-associated Nod2 variants.
 
Coauthors: Natasha E. Zachara, PhD2, Catherine L. Grimes, PhD1
1 University of Delaware, Newark, Delaware, United States
2 The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
 

Searching for Selective Reactions on Complex Molecular Scaffolds
Scott J. Miller, PhD, Department of Chemistry, Yale University

Natural products have provided perennial inspiration for the development of synthetic methods, and enzymes have provided an analogous platform for the conception of new catalysts. This lecture will recount an interplay of experiments stimulated by these two major classes of naturally occurring substances. Specifically, the discovery and use of peptides as catalysts for a variety of asymmetric bond formations will be presented. Likewise, applications of these catalysts to the synthesis and selective modification of complex molecules, including biologically active natural products, will be described. A particular emphasis will be placed on reactions that present unusual stereochemical challenges. An analysis of catalyst types that may be brought to bear on complex molecular environments will also be included.
 

Design and Synthesis of Cryptophane Biosensors for the Specific Detection of Cancer Cell Lines Using 129Xe NMR
Brittany A. Riggle, University of Pennsylvania, Department of Chemistry, Philadelphia, Pennsylvania, United States

Magnetic resonance imaging (MRI) is a versatile and commonly employed technique for the diagnosis of disease. However, because MRI typically utilizes endogenous proton signals, it suffers from poor contrast. As such, approximately half of all MRI procedures in humans are performed using gadolinium chelates, which effectively enhance contrast but do not readily identify biomolecular targets at sub-mM concentrations. Non-endogenous, hyperpolarized (HP) nuclei, such as 129Xe offer potential advantages in sensitivity and molecular specificity. Our lab has developed xenon biosensors exploiting the favorable association between 129Xe and water-soluble cryptophane cages. We have developed the highest xenon affinity cryptophanes measured to date; with association constants up to 42,000 M-1 at 298 K. By employing hyperpolarized chemical exchange saturation transfer (hyperCEST) we are able to reach picomolar detection limits for our cryptophane biosensors. Xenon biosensors also exploit the considerable NMR chemical shift sensitivity of 129Xe bound inside the cryptophane. This affords the possibility of designing a multitude of cryptophane conjugates that identify different cancer biomarkers in a biological specimen using 129Xe NMR spectroscopy. We have previously designed cryptophane conjugates that specifically target folate, integrin, and carbonic anhydrase receptors as well as matrix metalloproteinases that are over-expressed in many cancers. Here we describe a pH-responsive biosensor, which was designed to preferentially label cancer cells. Additionally, we are exploring the use of cryptophane as a biophysical probe for protein-protein interactions and conformational changes.
 
Coauthors: Yanfei Wang, Ivan J. Dmochowski, PhD
University of Pennsylvania, Department of Chemistry, Philadelphia, Pennsylvania, United States
 

A Radical SAM Enzyme that Crosslinks Unactivated Amino Acids
Kelsey R. Schramma, MA, Princeton University, Princeton, NJ, United States

Nature is very adept at transforming polypeptides into bioactive molecules employing a wide variety of strategies. These strategies, often seen in the biosynthetic pathways of bioactive secondary metabolites, are frequently utilized in the generation of macrocyclic peptides. One such cyclic peptide, streptide, was recently discovered in streptococcal bacteria and has been identified as a quorum sensing regulated secondary metabolite. Our lab has determined the structure of streptide, and identified the presence of an unprecedented carbon-carbon crosslink between the β-carbon of a lysine residue and the indole-C7 of a tryptophan side chain. Here we show that the formation of this novel carbon-carbon bond is catalyzed by a radical SAM enzyme, which we have termed StrB. We find that StrB contains two [4Fe-4S] clusters, one that activates SAM to generate the 5’-deoxyadenosyl radical, which initiates catalysis, and a second cluster, which is essential for catalytic activity. We further show that StrB installs the unusual Lys-to-Trp crosslink in a single step, thus providing a new route for peptide cyclization.  A mechanism for this unusual reaction is proposed.
 
Coauthors: Leah B. Bushin, BA, and Mohammad R. Seyedsayamdost, PhD
Princeton University, Princeton, NJ, United States
 

Application of New Technologies to Profile Substrates for Protein Methyltransferases
Chamara Senevirathne, PhD, Memorial Sloan-Kettering Cancer Center, New York, New York, United States

Protein Methyltransferases (PMTs) catalyzed methylation play a critical role in disease formation. Development of methods to identify methylation event in normal and diseased states is critical in order to fully characterize cell biology and treat many diseases including cancer. However, the current approaches are incapable of unambiguous profiling of the role of PMTs-catalyzed methylation event. Hence, new approaches are needed to explicitly characterize PMTs activities and substrates in cells, which will lead to understand the mode of action of methylation. Recently our lab has developed new biochemical tool, a Bioorthoganal Profiling of Protein Methylation (BPPM) methodology to unambiguously characterize the methylation events and targets in cells. In the current study, we developed a new method for substrate profiling of individual PMTs using BPPM coupled protein microarray technology. One of key findings demonstrates that the system is compatible with cell lysetes. This means that methyltransferases in their native state, which is important to maintain their activity in normal or disease state. We tested variety of engineered enzyme including PRMT1, PRMT2, G9a, SYMD3, and EZH2. On the other hand, we have developed another method on fluorous based separation for targets of methyltransferases. In this application fluorous tagged small molecule used to identify the methylation sites on peptides. The method will have great advantages over commonly used biotin-avidin based approaches. These methods thus allows us to map the methylation sites of many biologically-relevant targets and thus access the unprecedented accuracy to understand the downstream functions of these events.
 
Coauthor: Minkui Luo, PhD, Memorial Sloan-Kettering Cancer Center, New York, New York, United States
 

Controlling Sulfuryl-Transfer In Vivo One Compound at a Time
Ting Wang1

Sulfonation is a reversible modification that regulates the binding of endogenous and xenobiotic small-molecules to receptors, controls their half-lives and is intimately linked to human disease and drug efficacy. In humans, these reactions are catalyzed by a small (13 member) family of broad-specificity enzymes, the cytosolic sulfotransferases (SULTs). Here, molecular principles of SULT and nuclear-receptor ligand-specificity are used to create, for the first time, a design strategy that is capable of preventing the sulfation of a single compound in vivo without inhibiting SULTs or significantly altering the receptor-binding functions of the compound. Unlike classical inhibition approaches, this new strategy prevents sulfonation without inhibiting SULTs and thus maintains their homeostatic functions. The strategy is demonstrated for the nuclear-receptor family in an ex-vivo structure-activity study based on the scaffold of raloxifene (Evista®) - an FDA-approved nuclear-receptor agonist – and is shown to dramatically enhance the efficacy of apomorphine (an FDA-approved dopamine-receptor agonist) in zebrafish. The results indicate that sulfuryl-transfer and its attendant biology can now be controlled in vivo on a compound-by-compound basis. These concepts are expected to lead to new highly specific in vivo probes of sulfuryl-transfer biology, improvements in drug design and substantial enhancements in the efficacy of numerous FDA approved drugs.
 
Coauthors: Ian Cook1, Lei Feng3, Hua Wang2, Felix Kopp2, Peng Wu2, Florence Marlow3 and Thomas Leyh1
1 Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, United States
2 Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, United States
3 Department of Developmental & Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, United States
 

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