Bioorthogonal Chemistry in Biology and Medicine

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Bioorthogonal Chemistry in Biology and Medicine

Wednesday, December 11, 2013

The New York Academy of Sciences

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Innovations in chemistry have been essential for major breakthroughs in biology and medicine. At the heart of bioorthogonal chemical reactions is the development of uniquely reactive functional groups that allows specific covalent ligation of molecules in biological systems. Despite the challenges of performing specific chemical reactions in biological settings, a variety of bioorthogonal ligation methods such as native chemical ligation, Staudinger ligation and many cycloaddition reactions have been developed. The application of these bioorthogonal chemistries to biology through functionalized chemical reporters has enabled the imaging and large-scale analysis of nucleic acids, proteins, glycans, lipids and other metabolites in vitro as well as in vivo, in all kingdoms of life including bacteria, plants and mammals. In addition to monitoring biomolecules, bioorthogonal chemistry has allowed the functionalization of molecules for target identification of drugs and semi-synthesis of biomolecules for basic science as well as diagnostic and therapeutic agents. This symposium will highlight recent advances in bioorthogonal chemistry that have afforded unprecedented opportunities to explore biology and facilitated the synthesis of diagnostics and therapeutics for medicine. Oral and poster presentations will showcase ongoing applications and developments of bioorthogonal chemistry and discuss new frontiers and challenges for chemical biology.

*Networking reception to follow.

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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.


December 11, 2013

12:00 PM

Registration and poster set-up

12:30 PM

Welcome and Introduction
Jennifer Henry, PhD, The New York Academy of Sciences
Howard C. Hang, PhD, The Rockefeller University

12:40 PM

Chemical Reporters for Biological Discovery: Dissection of Protein S-Palmitoylation in Cellular Differentiation
Howard Hang, PhD, The Rockefeller University

1:15 PM

Early career investigator presentation
Photocaging the Staudinger Reagent for Increased Spatial and Temporal Control of the Chemoselective Reaction in vivo
Lisa Shah, SUNY Stony Brook

1:35 PM

Coffee Break and Poster Session

2:20 PM

Early career investigator presentation
Investigating γ-secretase Protein Interactions in Live Cells Using Active Site-directed Clickable Dual-photoaffinity Probes
T. Eric Ballard, PhD, Pfizer Worldwide Research and Development

2:40 PM

Implementing Bioorthogonal Chemistry to Interrogate Protein Methyltransferases As Epigenomic Regulators
Minkui Luo, PhD, Memorial Sloan-Kettering Cancer Center

3:15 PM

Keynote presentation
trans-Cyclooctene — a Stable, Voracious Dienophile for Bioorthogonal Labeling

Joseph M. Fox, PhD, University of Delaware

4:00 PM

Networking Reception and Poster Session

5:00 PM

Close

Speakers

Organizers

Howard C. Hang, PhD

The Rockefeller University

Dr Hang received his undergraduate degree in chemistry from the University of California, Santa Cruz, in 1998 with Prof. Joseph Konopelski and his PhD in chemistry from the University of California, Berkeley, in 2003 with Prof. Carolyn Bertozzi. He was a Damon Runyon Cancer Research Foundation postdoctoral fellow at Harvard Medical School and the Whitehead Institute for Biomedical Research with Prof. Hidde Ploegh. He joined Rockefeller in 2007 as assistant professor and head of laboratory and was appointed associate professor in 2013.

Jennifer S. Henry PhD

The New York Academy of Sciences

Speakers

T. Eric Ballard, Jr, PhD

Pfizer Worldwide Research and Development

Dr. Eric Ballard is a Principal Scientist in the Biotransformation group in Pharmacokinetics, Dynamics and Metabolism at Pfizer. In his current role, Eric investigates the clearance mechanisms and metabolism of small molecules in support of early and late stage research and development. Prior to his current position, Eric was a Postdoctoral Fellow in the Worldwide Medicinal Chemistry Group at Pfizer where he investigated the design and synthesis of clickable photoaffinity-based small molecule probes and their application to mechanism-of-action studies in neurologic and psychiatric disorders. Preceding his time at Pfizer, Eric was a Postdoctoral Associate in Prof. Timothy MacDonald's lab at the University of Virginia where he worked on the synthesis of small molecule inhibitors of the PFOR enzyme present in anaerobic pathogenic bacteria. Eric received his PhD in Organic Chemistry in 2008 from North Carolina State University under the direction of Prof. Christian Melander. He has coauthored numerous publications on organic synthesis, bioorganic chemistry, chemical biology and metabolism.

Joseph M. Fox, PhD

University of Delaware

Joseph M. Fox is Professor of Chemistry and Biochemistry at the University of Delaware.

Fox received his bachelor’s degree from Princeton University, where he conducted undergraduate research as a Pfizer fellow with Maitland Jones Jr. He completed graduate studies under Thomas Katz at Columbia University, where he developed a combined interest in materials science and the synthesis of challenging targets. He studied organometallic chemistry with Stephen Buchwald at MIT as an NIH postdoctoral fellow, where he worked on Pd-catalyzed ketone arylation and devised a synthesis of phosphine ligands that is now used commercially.

In 2001, Fox joined the faculty at UD, and he has built a multidisciplinary program that centers on the development of new types of chemical reactions. His group has developed new syntheses and transformations of chiral cyclopropenes and trans-cycloalkenes, and a new type of bioorthogonal reaction that allows for extremely rapid conjugation to biological macromolecules. Applications of this work include synthesis of naturally occurring and designed molecules with biological function, and in the use of design concepts in organic synthesis for applications in biology, nuclear medicine, imaging, therapy and materials science. He was promoted to the rank of Professor in 2011. His awards include the NSF Career Award and the University of Delaware Outstanding Doctoral Student Advising and Mentoring Award.

Howard C. Hang, PhD

The Rockefeller University

Dr Hang received his undergraduate degree in chemistry from the University of California, Santa Cruz, in 1998 with Prof. Joseph Konopelski and his PhD in chemistry from the University of California, Berkeley, in 2003 with Prof. Carolyn Bertozzi. He was a Damon Runyon Cancer Research Foundation postdoctoral fellow at Harvard Medical School and the Whitehead Institute for Biomedical Research with Prof. Hidde Ploegh. He joined Rockefeller in 2007 as assistant professor and head of laboratory and was appointed associate professor in 2013.

Minkui Luo, PhD

Memorial Sloan-Kettering Cancer Center

Dr. Luo is an Assistant Professor and Assistant Member in the program of Molecular Pharmacology and Chemistry Program at Memorial Sloan-Kettering Cancer Center. Dr. Luo received PhD from Princeton University with the major in bioorganic and chemical biology, and then conducted his postdoctoral training at Albert Einstein College of Medicine with the focus on developing tight-binding transition-state inhibitors. Dr. Luo accumulated multiple-year experiences to develop chemical tools to define, perturb and manipulate essential functions of enzymes. Dr. Luo has published more than 30 peer-reviewed papers in the field of chemistry and chemical biology in well-recognized peer-reviewed journals. He has also received many awards and honors, such as the Basil O'Connor Starter Scholar, NIH Director’s New Innovator Award, Alfred W. Bressler Scholar, and the V Scholar Award for Cancer Research.

Lisa Shah

SUNY Stony Brook

Lisa Shah received her BS in Chemistry from New York University in 2011 and is currently a doctoral candidate at Stony Brook University under the advisement of Dr. Isaac Carrico. She is a fellow of both the NIH-funded Chemical Biology Training Program and the US Department of State/New York Academy of Science NeXXt Scholars Program. Her research interests broadly and briefly include developing bioorthogonal chemical tools to probe biology, elucidating bacterial kinase signal transduction pathways, and understanding the role of PTMs in cancer cell biology.

Sponsors

Academy Friend

New England Biolabs

Promotional Partner

Nature


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

Chemical Reporters for Biological Discovery: Protein S-Palmitoylation in Cellular Differentiation and Innate Immunity
Howard Hang, PhD, The Rockefeller University

The advances in bioorthogonal chemistry has enabled the use of chemical reporters to image and retrieve nucleic acids, proteins, glycans, lipids and other metabolites in vitro, in cells as well as in whole organisms. By tagging these biomolecules, researchers can now monitor their dynamics in living systems and discover specific substrates of cellular pathways. These advances in chemical biology are providing important tools to characterize biological systems and human disease. To highlight these advances in bioorthogonal chemistry, I present recent work from our laboratory using chemical reporters to study protein S-palmitoylation, a reversible fatty acid protein modification, in cellular differentiation and innate immunity. I will also briefly summarize chemical reporters for other biomolecules and discuss future directions in the field.
 

Photocaging the Staudinger Reagent for Increased Spatial and Temporal Control of the Chemoselective Reaction in vivo
Lisa Shah, Department of Chemistry, SUNY Stony Brook

Bioorthogonal reactions are of great importance to scientists studying biomolecular function inside of living systems. The Staudinger Ligation is one such reaction known for being highly chemoselective, catalyst-free, and amide-bond forming, making it a logical choice for in vivo applications. However, oxidation of the phosphine reagent and slow kinetics in comparison to other bioorthogonal reactions limit its utility in a biological context. Here we describe a strategy that aims to address these aforementioned shortcomings by synthesizing a photocaged Staudinger reagent, DMNB-Phosphine-FLAG. We demonstrate that this photoactivatable probe is able to spatiotemporally label azide-bearing glycoproteins on fixed cells. To further validate its biological utility, future work is aimed at adapting DMNB-Phosphine-FLAG to spatiotemporally label cells in vivo in developing zebrafish. Light-mediated regulation coupled with the facile synthesis of alternative photocaged phosphine probes creates a highly regulatable, bioorthogonal process that would serve as a convenient and versatile tool for a number of in vivo applications.
 
Coauthor: Isaac S. Carrico, PhD, Department of Chemistry, SUNY Stony Brook
 

Implementing Bioorthogonal Chemistry to Interrogate Protein Methyltransferases as Epigenomic Regulators
Minkui Luo, PhD, Memorial Sloan-Kettering Cancer Center

Epigenetic regulations are involved in establishing cell-lineage diversity and the errors in these processes have been linked to many diseases including developmental abnormalities, neurological disorders and cancer. Among the key biochemical modifications in epigenetics is protein methylation, a process orchestrated by over 60 human protein methyltransferases (PMTs). Profiling targets and inhibitors of the PMTs is pivotal toward elucidating their roles in normal physiology and disease states. Unfortunately, conventional approaches are inefficient in these aspects. To address this challenge, our laboratory has developed a novel technology, which we termed as Bioorthogonal Profiling of Protein Methylation (BPPM). Here we engineered the SAM-binding pockets of designated PMTs to accommodate bulky SAM analogues. The engineered PMTs then tag distinct chemical moieties to the substrates of the designated PMTs, in conjunction with click chemical ligation, for target identification. We showed that the BPPM technology can readily reveal 100~2000 nonhistone substrates of individual PMTs and their biological functions have been linked to most essential biological pathways such as DNA replication, RNA processing, other posttranslational modulars and metabolic enzymes. We will exemplify several findings about unprecedented roles of PMTs such as regulation of transcription factors and RNA splicing factors.
 

trans-Cyclooctene— a stable, voracious dienophile for bioorthogonal labeling
Joseph M. Fox, PhD, University of Delaware

trans-Cycloalkenes have a rich physical organic chemistry, but until recently their practical applications in synthesis, biology and materials science had been limited. This seminar will describe the development and advancement of trans-cycloalkenes as tools for facilitating bioorthogonal labeling through reactions with s-tetrazines. Of the various click chemistries that have been pursued over the past decade, the tetrazine ligation enables the fastest reactivity. Described in this talk will be advances in computation and synthesis that have enabled the creation of coupling partners with rate constants in excess of k2 = 106 M–1s–1. After an overview of recent applications of tetrazine ligation to chemical biology and nuclear medicine will be a detailed discussion of recent applications to the field of biomaterials. Introduced will be the first example of interfacial bioorthogonal crosslinking—the use of bioorthogonal chemistry to create and pattern biomaterials for 3-D cell culture through diffusion-limited reactivity at the gel-liquid interface.
 

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