Chemical Biology Discussion Group Year-End Symposium

FREE

for Members

Chemical Biology Discussion Group Year-End Symposium

Tuesday, June 3, 2014

The New York Academy of Sciences

Presented By

 

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 Professor Michael Marletta of the Scripps Research Institute. 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.

* Lunch included.

Registration Pricing

Member$0
Student/Postdoc Member$0
Nonmember$40
Nonmember (Student / Postdoc / Resident / Fellow)$20

 


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


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

Agenda

* Presentation titles and times are subject to change.


June 3, 2014

9:30 am

Registration and poster set-up

10:00 am

Welcome and Introduction
Jennifer Henry, PhD, The New York Academy of Sciences
Brent R. Stockwell, PhD, Columbia University

10:10 am

A General Platform for Systematic Quantitative Evaluation of Small-Molecule Permeability in Bacteria
Tony D. Davis, BS, Tan lab, Weill Cornell Graduate School of Medical Sciences

10:30 am

Suppression of Aberrant Ras Activation in Cancer Cells with Synthetic Sos Mimics
Stephen Joy, MS, Arora lab, New York University

10:50 am

Synthesis of Dithioamide Peptides and Proteins and Their Application on Conformational Dynamic Study by Fluorescence Spectroscopy
Yun Huang, PhD, Petersson lab, University of Pennsylvania

11:10 am

Targeted Protein Destabilization in the Endoplasmic Reticulum Reveals an Estrogen-mediated Stress Response
Kanak Raina, MSc, Crews lab, Yale University

11:30 am

Networking Lunch Break and Poster Session
All poster presenters should stand by their posters 12:00–12:45 pm

1:00 pm

Cellular Metabolism Regulates Sensitivity to GPX4-Dependent Ferroptosis
Kenichi Shimada, MA, MPhil, Stockwell lab, Columbia University

1:20 pm

Nitrotyrosine as a Structural Switch in Designed Metalloproteins and Application as a Sensor for Tyrosine Nitration
Andrew Urmey, BS, Zondlo lab, University of Delaware

1:40 pm

Keynote Presentation:
Nitric Oxide Signaling: From Bugs to Humans
Michael Marletta, PhD, Scripps Research Institute

2:25 pm

Presentation of "Best Poster" awards

2:30 pm

Close

Speakers

Organizers

Brent R. Stockwell, PhD

Columbia University

Brent R. Stockwell, PhD is a tenured Associate Professor at Columbia University in the Departments of Biological Sciences and Chemistry, and is an Early Career Scientist of the Howard Hughes Medical Institute; he is also a member of Columbia's Herbert Irving Comprehensive Cancer Center, Motor Neuron Center, Stem Cell Initiative, Translational Neuroscience Initiative, and Institute for Data Sciences and Engineering. He serves as Director of the Columbia NYSTEM Chemical Probe Synthesis Facility, and co-Director of the Columbia High-Throughput Screening Center. His research involves the discovery of precision medicines that can be used to understand and treat cancer and neurodegeneration, with a focus on mechanisms governing cell death. These interdisciplinary investigations have led to new methods of small molecule drug discovery, and the discovery of drug candidates that act through a new form of cell death.

Professor Stockwell has received numerous awards, including a Burroughs Wellcome Fund Career Award at the Scientific Interface, a Beckman Young Investigator Award, the BioAccelerate NYC Prize, and the Lenfest Distinguished Columbia Faculty Award. He has trained 80 students, technicians and postdoctoral scientists, published 69 scientific articles, two book chapters, 37 patent applications, been awarded 14 US patents, and received 38 research grants for more than $13 million. He is also the author of The Quest for the Cure: The Science and Stories Behind the Next Generation of Medicines.

Jennifer S. Henry PhD

The New York Academy of Sciences

Keynote Speaker

Michael Marletta, PhD

The Scripps Research Institute

Michael A. Marletta received an AB degree in biology and chemistry from SUNY, College at Fredonia (1973), a PhD in 1978 from the University of California, San Francisco followed by a 2-year postdoctoral appointment at MIT. He was on the faculty at MIT then the University of Michigan. While at Michigan, he was appointed to the Howard Hughes Medical Institute. Marletta moved to the University of California, Berkeley in 2001 with appointments in Chemistry and MCB. In 2002 he was named the Aldo DeBenedictis Distinguished Professor of Chemistry in 2002. He served as Chair of the Department of Chemistry from 2005-2010. In July 2011 he joined the faculty of The Scripps Research Institute and was named President-Elect and Cecil and Ida Green Professor of Chemistry. He assumed the presidency in 1 January 2012.

Marletta has been recognized with: a MacArthur Fellowship (1995), election to the Institute of Medicine (1999), the American Academy of Arts and Sciences (2001), and the National Academy of Sciences (2006). He received the Harrison Howe Award (2004), the Repligen Award (2006) and the Esselen Award for Chemistry in the Public Interest (2006). Marletta's primary research interests lie at the interface of chemistry and biology with emphasis on the study of protein function and enzyme reaction mechanisms.

Speakers

Tony D. Davis, BS

Tan lab, Weill Cornell Graduate School of Medical Sciences

Tony D. Davis earned his Bachelor of Science degree in Biochemistry from Xavier University of Louisiana in 2007. While an undergraduate, Tony performed research with Professor Ruquia Ahmed-Schofield developing novel synthetic methods to access spirocyclic amine natural products. Tony is currently a graduate student in the lab of Professor Derek S. Tan at the Memorial Sloan Kettering Cancer Center. His thesis work focuses on developing cell-permeable inhibitors that target bacterial nonribosomal peptide synthetases and advancing an integrated platform to understand drug permeability in bacteria. After completing his graduate studies, Tony will pursue a Postdoctoral Fellowship in the lab of Professor Michael Burkart at the University of California, San Diego.

Stephen Joy, MS

Arora lab, New York University

Stephen Joy is a fifth year doctoral candidate at New York University. Born and raised in Evanston, IL, Stephen attended The University of Chicago where he studied atherosclerotic stress in carotid artery plaques under Dr. Angelo Scanu. Initially interested in becoming a medical doctor, Stephen shifted his focus to chemistry, even taking a position with The Princeton Review as an organic and general chemistry instructor. After graduating with a BS in chemistry in 2007, Stephen worked as a laboratory technician for UOP in Des Plaines for several years before joining Paramjit Arora's group at New York University in 2009. As a member of the Arora group, Stephen has focused on developing proteolytically-stable mimics of -helices to target protein–protein interactions such as Ras/Sos and p53/Mdm2.

Yun Huang, PhD

Petersson lab, University of Pennsylvania

Yun Huang obtained a Master degree in biochemistry from Lanzhou University, China, in 2008. He then moved to Prof. Gunter Fischer's group in the Max Planck Research Unit of Enzymology of Protein Folding in Germany, where he was working on the synthesis of selenoamide peptides and characterizing their photochemical and physicochemical properties and earned a PhD degree in 2013. He is currently a postdoctoral researcher in Prof. James Petersson's group at University of Pennsylvania. His current research interest is investigating the protein folding and misfolding by a combination of protein chemical synthesis and fluorescence spectroscopy.

Kanak Raina, MSc

Crews lab, Yale University

Kanak Raina received a Bachelor's degree in Chemistry at St. Stephen's College, New Delhi, and a Masters at IIT Kanpur, India. He is currently a graduate student in the lab of Prof. Craig Crews in the Molecular, Cellular, and Developmental Biology department at Yale University, where his work centers on discovery and characterization of small molecule modulators of the Unfolded Protein Response.

Kenichi Shimada, MA, MPhil

Stockwell lab, Columbia University

Kenichi Shimada is a Ph.D. candidate in the Department of Biological Sciences at Columbia University. He received B.A. and M.A. from the University of Tokyo, Japan, where he studied molecular biology of Duchenne muscular dystrophy under Dr. Ryoichi Matsuda. Before joining the Ph.D. program at Columbia, Kenichi served as a bioinformatician at HuBit Genomix, Inc., a biotech venture engaged in SNP analysis of Japanese cohorts. Since he joined the laboratory of Dr. Brent Stockwell in 2008, Kenichi has been focusing on elucidating the mechanism of ferroptosis, an iron-dependent oxidative cell death that occurs in certain cancers and pathologies.

Andrew Urmey, BS

Zondlo lab, University of Delaware

Drew Urmey is a 2nd-year graduate biochemistry student at the University of Delaware. He received his BS in Biochemistry and Molecular Biology at the University of Maryland, Baltimore County where he worked in the Karpel laboratory studying single-stranded DNA binding proteins. Drew currently works in the Zondlo lab at UD, where he studies the effects of modified/non-canonical residues in peptides, with a primary interest in protein design.

Sponsors

Promotional Partners

The Chemical Biology Consortium — A New NCI Initiative

International Chemical Biology Society

Nature

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

Nitric Oxide Signaling: From Bugs to Humans
Michael Marletta, PhD, The Scripps Research Institute

Nitric oxide (NO) has long been known to be an intermediate in bacterial pathways of denitrification. It is only since the middle to late 1980s that it was found to play a central role in a much broader biology context. For example, it is now well established that NO acts as a signaling agent in higher organisms. Yet NO is toxic and reactive under biological conditions. How is the biology carried out by NO controlled? How is NO used and the inherent toxicity avoided? How do organisms tell the difference between NO and O2? What is the biological output? A molecular perspective on ligand discrimination in hemoproteins has emerged as has a further understanding and predictions about selective ligand sensing and function in biology.

A General Platform for Systematic Quantitative Evaluation of Small-molecule Permeability in Bacteria
Tony D. Davis, BS, Tan lab, Weill Cornell Graduate School of Medical Sciences

The chemical features that impact small-molecule permeability across bacterial membranes are poorly understood, and the resulting lack of tools to predict permeability presents a major obstacle to the discovery and development of novel antibacterials. Antibacterials are known to have vastly different structural and physicochemical properties compared to non antiinfective drugs, as illustrated herein by principal component analysis (PCA). To understand how these properties influence bacterial permeability, we have developed a systematic approach to evaluate penetration of diverse compounds into bacteria. Intracellular compound accumulation is quantitated using LC-MS/MS, then PCA and Pearson pairwise correlations are used to identify structural and physicochemical parameters that correlate with accumulation. An initial study using ten sulfonyladenosines in three bacteria with structurally distinct cellular envelopes has revealed that the impacts of several physicochemical parameters upon permeability and efflux sensitivity differ among the various bacteria in a non-obvious manner. This sets the stage for use of this platform in larger analyses to identify global relationships between chemical structure and bacterial permeability that would enable the development of predictive tools to accelerate antibiotic drug discovery.

Suppression of Aberrant Ras Activation in Cancer Cells with Synthetic Sos Mimics
Stephen Joy, MS, Arora lab, New York University

Aberrant activation of the small GTPase Ras by Sos-mediated nucleotide exchange can arise through diverse processes including oncogenic mutation of Ras or constitutive receptor tyrosine kinase (RTK) signaling. The resulting deregulation of cellular physiology impacts the growth and survival of ~30% of all human tumors. Recent evidence supports the therapeutic strategy of targeting aberrant Ras activity by blocking the Ras-Sos catalytic interaction, the rate-limiting step in canonical Ras activation. Here, we describe a synthetic mimic of the Ras-binding domain of Sos that inhibits Ras activation with high potency. Treatment of Ras-transformed cancer cells with the inhibitor suppressed the GTP loading of both wild-type and mutant oncogenic Ras proteins, and reduced the viability of a panel of cancer cell lines. Our studies with the direct inhibitor of Ras provide mechanistic insights regarding the role of the Ras-Sos interaction in maintaining oncogenic signaling. DNA content analysis reveals that the Ras inhibitor causes alterations to the cell cycle and engenders an apoptotic cell fate—a result that supports recent findings in Ras-transformed cancer cells where the wild-type Ras protein is post-transcriptionally silenced. Lastly, we show that the synthetic Sos mimics are transported into cells through macropinosomes, and demonstrate the exploitation of oncogene-stimulated macropinocytosis for specific targeting of cancer cells.

Synthesis of Dithioamide Peptides and Proteins and Their Application on Conformational Dynamic Study by Fluorescence Spectroscopy
Yun Huang, PhD, Petersson lab, University of Pennsylvania

Tracking protein conformational change is important to understand the folding and function of proteins. Förster resonant energy transfer (FRET) and photoinduced electron transfer (PET) are widely used to glean time-resolved structural information on protein motions. However, the relatively large size of fluorophores and quenchers may introduce significant perturbation on the protein structure. The thioamide bond, only one atom substitution to peptide bond, has recently been shown to represent the minimalist fluorescent quencher over various fluorophores by photo-induced electron transfer (PET) mechanism. Unlike commonly used fluorescence quenchers, thioamides are sufficiently small that they can be placed at nearly any position of the protein sequence without significantly altering the secondary structure. However, the moderate quenching efficiency may limit its sensitivity for application. Here, we show that two consecutive thioamide bonds could be incorporated into peptides and proteins, and the quenching effect is further strengthened compared with the mono-thioamide system. The dithioamide bonds thus provide increased sensitivity to detect the protein conformation changes.

Targeted Protein Destabilization in the Endoplasmic Reticulum Reveals an Estrogen-mediated Stress Response
Kanak Raina, MSc, Crews lab, Yale University

Accumulation of unfolded proteins within the endoplasmic reticulum of eukaryotic cells leads to an unfolded protein response (UPR) that either restores homeostasis or commits the cell to apoptosis. Tools traditionally used to study the UPR are unfortunately pro-apoptotic and thus confound analysis of long-term cellular responses to endoplasmic reticulum stress. Here, we describe an Endoplasmic Reticulum-localized HaloTag (ERHT) protein that can be conditionally destabilized using a small molecule hydrophobic tag (HyT36). Treatment of ERHT-expressing cells with HyT36 induces an acute, resolvable endoplasmic reticulum stress that results in transient UPR activation without induction of apoptosis. Transcriptome analysis of late-stage responses to this UPR stimulus revealed a link between UPR activity and estrogen signaling: UPR signaling induces estrogen receptor transcriptional activity, which modulates future sensitivity to endoplasmic reticulum stress. Estrogen receptor activation desensitizes MCF7 cells to endoplasmic reticulum stress, whereas, conversely, estrogen receptor inhibition sensitizes MCF7 cells to endoplasmic reticulum stress. Finally, estrogen receptor inhibition in multiple myeloma cell lines sensitized them to UPR activation and apoptosis induced by the proteasome inhibitor, epoxomicin. Our data suggest that estrogen signaling may play a role in the adaptive UPR, and manipulating this interaction may have therapeutic applications in the treatment of multiple myeloma.

Cellular Metabolism Regulates Sensitivity to GPX4-Dependent Ferroptosis
Kenichi Shimada, MA, MPhil, Stockwell lab, Columbia University

Abstract not available.

Nitrotyrosine as a Structural Switch in Designed Metalloproteins and Application as a Sensor for Tyrosine Nitration
Andrew Urmey, BS, Zondlo lab, University of Delaware

Tyrosine nitration is a specific, non-enzymatic post-translational modification associated with disease states and oxidative/nitrosative stress. Nitric oxide is produced as a signaling molecule and as a cytotoxic defense molecule in inflammation; this molecule generates other reactive nitrogen species (RNS) which can modify tyrosine to 3-nitrotyrosine via radical chemistry, potentially changing the structure and function of affected proteins. Nitrotyrosine is present in anionic and neutral states at physiological pH, with properties which vary significantly from native tyrosine and from each other. While it is a biomarker for various pathologies including Alzheimer's disease, methods for detection of nitrotyrosine are limited. To better understand tyrosine nitration, we have designed a series of 14- to 18-residue peptides which use tyrosine nitration as a structural switch upon metal binding. The designs are based on a Ca2+-binding EF-hand motif, in which a native glutamate essential for metal binding is changed to tyrosine; if nitrated, the resultant nitrotyrosine (pKa~7) can mimic glutamate and coordinate metals in a bidentate fashion using the nitro group and phenolate oxygen. Compared to unmodified tyrosine, nitrotyrosine-containing peptides exhibited 20- to >100-fold increases in Tb3+ affinity. We concurrently designed a genetically encodable, "turn-off" fluorescent sensor of tyrosine nitration. In this sensor, tryptophan sensitizes Tb3+ emission via a FRET-like mechanism; if tyrosine is nitrated, however, it can both displace Glu16 to enhance binding and quench the energy transfer to completely abrogate emission by the bound metal, with nitration causing a 35-fold decrease in terbium luminescence versus unmodified peptide.

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