Click Chemistry in Biology and Medicine: New Developments and Strategies

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Click Chemistry in Biology and Medicine: New Developments and Strategies

Monday, September 15, 2014

The New York Academy of Sciences

Presented By

 

Inspired by the complexity that nature achieves from a just handful of building blocks, K. Barry Sharpless began looking for a reliable method for discovering new chemical connectivity in the mid-1990s. In 1998 he coined the now-familiar term "click chemistry". The three 'perfect' click chemistry reactions — copper-catalyzed azide-alkyne cycloaddition (CuAAC), thiol-ene reaction, and sulfur(VI) fluoride exchange (SuFEx) — offer a method with far-reaching potential in drug discovery and biomedical research. This symposium explores recent developments in click chemistry, including the discovery of new click reactions, which address fundamental challenges in biology and provide new technologies for disease diagnosis and therapy. The symposium brings together pioneers in the field and young academic investigators from the tri-state area. Late-breaking oral abstract presentations will be given, and a poster session will highlight the breadth and depth of cutting-edge research currently underway.

*Reception to follow.

Registration Pricing

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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 times are subject to change.


Monday, September 15, 2014

11:30 am

Registration and Poster Set-up

12:00 pm

Welcome and Introduction
Jennifer Henry, PhD, The New York Academy of Sciences
Peng Wu, PhD, Albert Einstein College of Medicine

12:15 pm

Targeting Immune Cells with Siglec Ligand Decorated Nanoparticles
Jim Paulson, PhD, The Scripps Research Institute

1:00 pm

A Chemical Technology for Deconstructing Redox Signaling
Yimon Aye, PhD, Cornell University

1:30 pm

Late-Breaking Abstract Presentation: Non-hydrolyzable Analogs and Affinity Reagents to Elucidate Diphosphoinositol Polyphosphates Signaling
Mingxuan Wu, MS, Princeton University

1:45 pm

Networking Coffee Break

2:15 pm

New Methods to Visualize Glycans in Living Systems and Human Samples
Peng Wu, PhD, Albert Einstein College of Medicine

2:45 pm

Using Small Molecules to Engineer and Explore Human Immunity
David A. Spiegel, PhD, MD, Yale University

3:15 pm

A New "Perfect" Click Reaction: CuAAC has a Sibling
K. Barry Sharpless, PhD, The Scripps Research Institute

4:00 pm

Closing Remarks
Peng Wu, PhD, Albert Einstein College of Medicine
 
Networking Reception

5:00 pm

Close

Speakers

Organizers

Peng Wu, PhD

Albert Einstein College of Medicine

Peng Wu is an Associate Professor in the Department of Biochemistry and the Director of the newly established Chemical Biology Core Facility at the Albert Einstein College of Medicine. He received his doctorate from the Scripps Research Institute in 2005 under the guidance of Professor K. Barry Sharpless. From September 2004 to early 2005, he was a visiting student in the laboratory of Professor Craig J. Hawker at IBM Almaden Research Center and at the University of California, Santa Barbara. From August 2005 to September 2008, Dr. Wu was a postdoctoral fellow in the group of Professor Carolyn R. Bertozzi at the University of California, Berkeley. Joining the Albert Einstein College of Medicine in October 2008, Dr. Wu is developing a research program at the interface of chemistry and biology, with a focus on the invention of new tools for studying protein glycosylation, especially those related to human disease.

Jennifer Henry, PhD

The New York Academy of Sciences

Keynote Speakers

Jim Paulson, PhD

The Scripps Research Institute

James C. Paulson obtained his PhD (Biochemistry) in 1974 from the University of Illinois at Champaign–Urbana, and did post-doctoral work at Duke University Medical Centre, in Durham, North Carolina from 1974–78. From 1978–1990 he rose from Assistant Professor to full Professor and vice-chair in the Department of Biological Chemistry at the UCLA School of Medicine where he developed an interest in analysis of receptor specificity of influenza viruses from different host species. From 1990–1999 he served as Vice President and Member Board of Directors of Cytel Corporation, La Jolla, CA. From 1999–present he has been Professor at the Scripps Research Institute, in La Jolla, California, where he is currently Chair of the Department of Cell and Molecular Biology with joint appointments in the Departments of Chemical Physiology, and Immunology and Microbial Sciences. His current research interests include the roles of glycan binding proteins in the modulation of immune cell signaling, and the receptor specificity of mammalian and animal influenza viruses.

K. Barry Sharpless, PhD

The Scripps Research Institute

Descended from one of the original land purchasers in William Penn’s New World venture, K. Barry Sharpless received a Quaker education at the Friends Central School, Haverford, Pennsylvania. In 1963 he graduated from Dartmouth College, where he was introduced, most fortuitously, to the wonders of chemistry by T. A. Spencer. Following graduate research with E. E. van Tamelen at Stanford University, Sharpless completed postdoctoral studies with J. P. Collman, also at Stanford, and at Harvard University with Konrad Bloch. Sharpless set up his own laboratory in 1970 at the Massachusetts Institute of Technology. Except for several years in the 1970s when he was a member of Stanford’s chemistry faculty, Sharpless remained at MIT until moving to the Scripps Research Institute (TSRI) in 1990. At TSRI he is W. M. Keck Professor of Chemistry and a member of the Skaggs Institute for Chemical Biology. In 2011 Thomson Reuters named the top 100 chemists whose papers published in the first decade of the 21st Century achieved the highest citation impact scores: Sharpless was #4.

Speakers

Yimon Aye, PhD

Cornell University

Yimon Aye received her undergraduate degree in Chemistry from University of Oxford, UK, in 2004; and her doctoral degree in Organic Chemistry from Harvard University, MA, USA, in 2009 (under the guidance of Professor David Evans). As a Damon Runyon cancer research postdoctoral fellow, she received training in mechanistic biology at Massachusetts Institute of Technology, MA, USA (mentored by Professor JoAnne Stubbe). She is presently the Milstein junior faculty fellow and assistant professor at the Department of Chemistry & Chemical Biology, Cornell University, Ithaca, USA, with secondary appointment at the Department of Biochemistry, Weill Cornell Medical College, New York, NY, USA. The Aye Lab at Cornell University was established in July 2012 and was recently recognized by the NSF CAREER and the Beckman Young Investigator Awards.

David A. Spiegel, MD, PhD

Yale University

David Spiegel, MD, PhD is an Associate Professor at Yale University with appointments in the departments of Chemistry and Pharmacology. He graduated Magna Cum Laude in Chemistry from Harvard University in 1995, having worked in the laboratory of Professor Yoshito Kishi. He then went on to pursue a combined MD/PhD degree at the Yale University MD/PhD program, where he worked in the laboratory of Professor John L. Wood, focusing on synthetic organic chemistry, and graduating in 2005. After a brief postdoctoral stint at the Broad Institute of Harvard and MIT under Professor Stuart L. Schreiber, Professor Spiegel started his independent academic career at Yale University in 2007.

The Spiegel research group (www.spiegelgroup.yale.edu) focuses in the area of Synthetic Immunology, which involves the development of novel synthetic systems for modulating and manipulating immune function. Specific disease areas of interest include prostate cancer, HIV, Gram-positive bacteria, and aging. Professor Spiegel has served as a consultant for International Flavors and Fragrances, Novartis Institute for Biomedical Research, Bristol-Myers Squibb, and Pharmaseq. He has also been recognized with various awards and honors, including the NIH Director’s New Innovator Award, the Department of Defense Era of Hope Scholar Award, the Ellison Medical Foundation New Scholar Award in Aging Research, the Novartis Early Career Award in Organic Chemistry, the Bill and Melinda Gates Foundation Grand Challenges Explorations Award, an Alfred P. Sloan Foundation Fellowship, and others.

Mingxuan Wu, MS

Princeton University

Mingxuan Wu was born in Zhengzhou, the capitol city of Henan Province in central China. He received his BS in biotechnology and MS in microbiology from Shanghai Jiao Tong University. Under the direction of Professor Huchen Zhou in School of Pharmacy, he synthesized sugar nucleotides to study antibiotic glycosylation and diterpenoid probes to elucidate the mechanism of leukemia cells differentiation. In 2010, he joined Fiedler lab in Department of Chemistry at Princeton University to study diphosphoinositol polyphosphate signaling by non-hydrolyzable analogs and affinity reagents.

Peng Wu, PhD

Albert Einstein College of Medicine

Peng Wu is an Associate Professor in the Department of Biochemistry and the Director of the newly established Chemical Biology Core Facility at the Albert Einstein College of Medicine. He received his doctorate from the Scripps Research Institute in 2005 under the guidance of Professor K. Barry Sharpless. From September 2004 to early 2005, he was a visiting student in the laboratory of Professor Craig J. Hawker at IBM Almaden Research Center and at the University of California, Santa Barbara. From August 2005 to September 2008, Dr. Wu was a postdoctoral fellow in the group of Professor Carolyn R. Bertozzi at the University of California, Berkeley. Joining the Albert Einstein College of Medicine in October 2008, Dr. Wu is developing a research program at the interface of chemistry and biology, with a focus on the invention of new tools for studying protein glycosylation, especially those related to human disease.

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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

Abstracts

Targeting Immune Cells with Siglec Ligand Decorated Nanoparticles
James C. Paulson, The Scripps Research Institute, La Jolla, CA

The sialic acid binding immunoglobulin lectin family of cell adhesion receptors called siglecs are differentially expressed on white blood cells that confer both innate and adaptive immune responses. Because they recognize sialic acid containing glycans expressed on all mammalian cells, siglecs are increasingly recognized as receptors that help the immune system distinguish between self and non-self. To study the functions of siglecs in immune cells, we have developed a nanoparticle platform decorated with analogs of their glycan ligands that target siglec-expressing cells in vivo. The challenge has been to identify ligands of high specificity and avidity to bind to a single member of the siglec family, which now comprise 14 members in humans and 9 in mice. To accomplish this we generated a diverse library of analogs using a high-throughput strategy employing CuAAc click chemistry to introduce substituents at the C-9 and C-5 positions of sialic acid. Each siglec was then screened for their specificity against the library using glycan microarrays to identify ligands of high avidity and that react with a single siglec. To date ligands suitable for in vivo targeting of various white blood cells have been identified for nine different human and murine siglecs. Using these ligands we have demonstrated the utility of siglec ligand decorated nanoparticles for in vivo targeting siglec expressing cells in applications that include delivery of chemo-therapeutic agents to B lymphoma cells, delivery of antigens to macrophages, and induction of B cell tolerance. (NIH grants AI050143, AI099141, CA013889 and HFSP Fellowship LT001099/2010-L).
 

Coauthors: Matthew S. Macauley, Ryan McBride, Corwin M. Nycholat, Fabian Pfrengle, Christoph Rademacher, Cory D. Rillahan, The Scripps Research Institute, La Jolla, CA
 

A chemical technology for deconstructing redox signaling
Yimon Aye, Cornell University

The ability to dissect multicomponent signaling networks has been the bedrock of numerous biomedical breakthroughs. Despite the emerging importance of redox-dependent cell signaling, studying the regulatory roles of reactive diffusible small-molecule messengers remains devilishly difficult. The only general way to study the consequences of redox events has been through "multi-hit" approaches in which the entire specimen is treated with a reactive entity. Multi-hit strategies have yielded important information about stress-associated pathways, but hitting many targets trips many signaling switches simultaneously. Consequently, functional links between upstream modifications on specific targets and downstream response remain unknown. The impact of a single redox event on a single target has thus been completely unaddressed. My laboratory has introduced a new way to selectively flip a single redox switch in cells at a precise time by selective perturbation with redox-derived signaling electrophiles. This talk describes an application of our new methodology in target-specific cell activation that triggers single redox events at a specific protein target, and shows that modest modifications on a single target are sufficient to elicit a pharmaceutically important response downstream. The data suggest that our chemistry-driven targeted perturbation approach is an exciting first step to understanding specificity along individual redox signaling trajectories.
 

Late-Breaking Abstract Presentation: Non-hydrolyzable Analogs and Affinity Reagents to Elucidate Diphosphoinositol Polyphosphates Signaling
Mingxuan Wu, MS, Princeton University

The diphosphoinositol polyphosphates (PP-IPs) are a central group of eukaryotic messengers. They regulate numerous processes, including telomere maintenance, cellular energy homeostasis, chromatin remodeling and adaptation to environmental stresses. To date, most of the molecular details in PP-IP signaling have remained elusive, due to a lack of appropriate methods and reagents. Here we describe the expedient synthesis of methylenebisphosphonate PP-IP analogues. Their characterization revealed that the analogues exhibit significant stability and mimic their natural counterparts very well. This was further confirmed in two independent biochemical assays. In addition, the analogs can also be used as mechanistic probes, to distinguish between the two distinct signaling mechanisms, protein binding and protein pyrophosphorylation. We also have synthesized affinity reagents of PP-IPs analogs to identify their binding proteins to study signaling mechanisms. The non-hydrolysable PP-IPs thus emerge as important tools and hold great promise for a variety of applications.
 

A New "Perfect" Click Reaction
K. Barry Sharpless, PhD, The Scripps Research Institute

Sulfur(VI) Fluoride Exchange (SuFEx) chemistry forges rugged inorganic links between carbon centers (C-O-SO2-O-C). Like most click reactions, it is an old process with a rich and instructive history. We surveyed that history and discovered new improvements that allow the underappreciated sulfate connection to be made for drug discovery and polymer fabrication.
 

Using Small Molecules to Engineer and Explore Human Immunity
David A. Spiegel, MD, PhD, Yale University

Antibody-based therapeutics have become critical instruments in treating diseases ranging from rheumatoid arthritis to cancer in recent years. However, antibodies and other therapeutic proteins are limited in therapeutic applications by their chemical structures: because they are peptide-based, they require intravenous administration, are often highly immunogenic or allergenic, and treatment regimens are often very costly.
 
This talk describe recent research efforts in our laboratories toward the design, chemical synthesis, and biological characterization of small molecule antibody recruiting therapeutics against prostate cancer, Staphylococcus aureus, and the human immunodeficiency virus (HIV). These are bifunctional small molecules designed to redirect antibodies already present in the human bloodstream to the surfaces of pathogenic cells, such as cancer cells, bacteria, and virus particles. The ternary complex formed between these agents, endogenous antibodies, and target cells will lead to immune-mediated pathogen destruction. In theory, this strategy would exploit many of the advantages of biologics, while circumventing the disadvantages, by capitalizing on the chemical properties of small molecules (e.g., high oral bioavailability, facile synthesis, and low cost). It is our hope that this small molecule-based strategy will serve as starting point toward entirely novel scientific insights and therapeutic approaches relevant to a wide range of disease states.
 

New Methods to Visualize Glycans in Living Systems and Human Samples
Peng Wu, Albert Einstein College of Medicine

Diseased cells have characteristic, aberrant expression of cell-surface glycans that are under-studied due to a lack of specific methods for their detection. In this talk, I will discuss our progress on using chemoenzymatic methods that combine the specificity of glycan modification enzymes and the fidelity of bioorthogonal click chemistry to imaging cancer associated glycans in living organisms and human samples.
 

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