Chemical Biology Discussion Group Year-End Meeting

FREE

for Members

Chemical Biology Discussion Group Year-End Meeting

Tuesday, June 8, 2010

The New York Academy of Sciences

The Chemical Biology Discussion Group brings together chemists and biologists interested in learning about the latest ideas in this rapidly growing field. It provides a forum for lively discussion and for establishing collaborations between chemists armed with novel technologies and biologists receptive to using these approaches to solve their chosen biological problems. This year-end meeting features a prominent keynote speaker and carefully selected junior researchers to showcase their work.

Agenda

Computationally Guided Drug Discovery
Bill Jorgensen, Yale University

Chemical Tailoring of Mammalian Viral Vectors via the Incorporation of Unnatural Sugars and Amino Acids
Partha Banerjee, Stony Brook University

Effort Toward the Total Synthesis of Aconitine Norditerpenoid Alkaloid 9-Deoxylappaconitine
Yuan Shi, Memorial Sloan Kettering Cancer Center

Analysis of Helix-Mediated Protein-Protein Interactions for Potential Therapeutic Intervention
Andrea Jochim, NYU

A Heritable Mutagenesis System for Directed Evolution Entirely Within Living Cells
Dante Romanini, Columbia University

Discovery of Antibacterial Virulence Inhibitors Targeted at Type III Protein Secretion
Kelvin Lun Tsou, The Rockefeller University

Exploiting redundancy in the genetic code: control of pathogen virulence via computationally designed genetic material
J. Robert Coleman, Albert Einstein College of Medicine and Montefiore Medical Center

Networking Reception

Speakers

Organizers

Yingkai Zhang

New York University

Jennifer Henry, PhD

The New York Academy of Sciences

Speakers

Bill Jorgensen, PhD

Yale University

Bill Jorgensen is a graduate of Princeton and Harvard, spent 15 years on the faculty at Purdue, and in 1990 moved to Yale, where he is a Sterling Professor and Director of the Division of Physical Sciences and Engineering. Bill's research has combined quantum, statistical, and molecular mechanics to study chemistry in solution. He has been a leader in computational studies of organic and enzymatic reactions in solution, molecular recognition, protein-ligand binding, and molecular properties. His OPLS force fields and TIPnP water models are widely used. Bill's research group is also actively engaged in de novo drug design and synthesis, particularly for anti-infective, anti-proliferative, and anti-inflammatory agents. Among honors, Bill has received an ACS Cope Scholar Award, the ACS Award for Computers in Chemical and Pharmaceutical Research, AAAS and ACS Fellowships, the ISQBP Award in Computational Biology, the PSJ Sato International Award, and membership in the American Academy of Arts & Sciences. He is a founder of Rib-X Pharmaceuticals and Editor of two ACS journals, Journal of Chemical Information and Modeling and the Journal of Chemical Theory and Computation.

Partha Banerjee

Stony Brook University

Partha completed his BS from St Stephens College, New Delhi and his MS from the University of Delhi in 2005. He then spent a year in the lab of Dr. Y. Singh at the Institute of Genomics and Integrative Biology, New Delhi working with nucleoside diphosphate kinase mutants of Bacillus anthrasis and studying its effects on spore formation. He then joined the State University of New York at Stony Brook in the fall of 2006 to pursue his PhD in Chemistry, where he has since been working with Dr. Isaac Carrico. His research includes tailoring mammalian vectors with non-natural amino acids and sugars and developing novel gene delivery agents.

Yuan Shi

Memorial Sloan Kettering Cancer Center

Yuan Shi graduated with a BS degreee in chemistry from University of Science and Technology of China (USTC) in 2004. After undergraduate school, he came to the US and joined David Gin's research group in 2004, at the University of Illinois at Urbana Champaign. In 2006 the Gin group moved Memorial Sloan Kettering Cancer Center, and he remained there as a graduate student.

Andrea Jochim

NYU

Andrea Jochim is a graduate of Cal Poly, San Luis Obispo, where she received her BS in chemistry and biochemistry in 2003. She is currently in her final year of graduate studies in the PhD program at New York University; her research interests span computational and experimental aspects of chemical biology.

Dante Romanini

Columbia University

Dante Romanini received his BS in Chemistry from Carnegie Mellon University in 2003. His undergraduate thesis described the discovery of hybrid aptamers consisting of both DNA and peptide nucleic acids (PNA). He then undertook graduate studies at the University of California, Berkeley in the laboratory of Prof. Matthew Francis. While there he developed new peptide-protein coupling methods and applied those methods to the construction of targeted nanostructures for magnetic resonance imaging and positron emission tomography (PET). He was a member of the Chemical Biology Graduate Program at Berkeley, and he received a Ph.D. in Chemistry in 2008. He then moved to the laboratory of Prof. Virginia Cornish at Columbia University, where he is currently an NIH Postdoctoral Fellow researching new methods for directed evolution.

Kelvin Lun Tsou, PhD

The Rockefeller University

Kelvin Tsou earned a BS degree in Chemistry with Honors from the University of North Carolina at Chapel Hill in 2002. His undergraduate research was under the supervision of professor Marcey Waters to investigate the energetics of cation–π interactions in aqueous media using α-helix models. Under the direction of professor Andrew Hamilton, his PhD research at Yale involved the development of protein surface receptors based on macrocyclic scaffolds for modulation of protein–protein interactions. Currently in professor Howard Hang’s lab at Rockefeller University, Kelvin works on the development of antibacterial agents targeting Type III Secretion System by the Gram negative bacteria.

J. Robert Coleman, PhD

Albert Einstein College of Medicine

Dr. J. Robert Coleman received his undergraduate degree from Tulane University in Cell and Molecular Biology. At Tulane, he studied transcription factor regulation of early developmental processes in the chicken embryo. Dr. Coleman then attended Stony Brook University, where he participated in innovative research in the field of infectious disease, receiving his Ph.D. in Molecular Genetics and Microbiology in 2008. At Stony Brook, his dissertation work was conducted in the Laboratory of Dr. Eckard Wimmer, a scientist whose work is at the crossroads of virology and synthetic biology, pushing the envelope of innovation. Dr. Coleman’s thesis focused on synthetically designing poliovirus genomes. These designed viruses were attenuated and the resulting synthetically modified strains could be utilized as templates for vaccine development. Recently, the model developed by this work has been successfully applied to Influenza A virus.

Dr. Coleman is currently a post-doctoral fellow in the laboratory of Dr. Liise-anne Pirofski at the Albert Einstein College of Medicine in the Department of Medicine, Division of Infectious Disease. Dr. Pirofski’s laboratory studies the bacterial pathogen Streptococcus pneumoniae, yielding significant findings on the host response to this pathogen. Dr. Coleman joined Dr. Pirofski’s laboratory seeking to apply synthetic gene customization to bacterial genetics, while simultaneously learning bacterial pathogenesis and host immunity under her tutelage.

Abstracts

Computationally Guided Drug Discovery

Bill Jorgensen, PhD, Yale University

Drug development is being pursued through computer-aided structure-based design. For de novo lead generation, the BOMB program builds combinatorial libraries in a protein binding site using a selected core and substituents, and QikProp is applied to filter all designed molecules to ensure that they have drug-like properties. Monte Carlo/free-energy perturbation simulations are then executed to refine the predictions for the best scoring leads including ca. 1000 explicit water molecules and extensive sampling for the protein and ligand.

FEP calculations for optimization of substituents on an aromatic ring and for choice of heterocycles are now common. Alternatively, docking with Glide is performed with large databases of purchasable compounds to provide leads, which are then optimized via the FEP-guided route. Successful application has been achieved for HIV reverse transcriptase, FGFR1 kinase, and macrophage migration inhibitory factor (MIF); micromolar leads have been rapidly advanced to extraordinarily potent inhibitors.

Chemical Tailoring of Mammalian Viral Vectors via the Incorporation of Unnatural Sugars and Amino Acids

Partha Banerjee, Stony Brook University

Virothapy applications have been limited by the lack of general, efficient and non-perturbing methods to alter virus surface functionality. Genetic methods generally perturb virus physiology and lack access to many desirable effector molecules, whereas traditional chemical modifications lack the control of genetics. Here we demonstrate a two step labeling technique of adenoviral virus capsid proteins, an initial metabolic “prelabeling” with unnatural substrates during virus production that allows subsequent access to highly selective bioorthogonal reactions facilitating the attachment of a variety of effector functionality onto the coat proteins. The metabolic incorporation of the unnatural substrates demonstrates no significant impact on virus production or infectivity. This novel technique utilizes a non-natural sugar, N-azidoacetylgalactosamine and an amino acid moiety, azidohomoalanine to substitute N-acetylglucosamine and methionine residues respectively in the virus coat protein makeup. Copper catalyzed “Click” and Staudinger ligation reactions have been used to append a variety of probes to solvent exposed azides. Modification of the incorporated azide functionality with cancer selective targeting ligands demonstrates markedly increased gene delivery in breast cancer cell lines.

Effort Toward the Total Synthesis of Aconitine Norditerpenoid Alkaloid 9-Deoxylappaconitine

Yuan Shi, Memorial Sloan Kettering Cancer Center

Aconitine norditerpenoid alkaloids are a large family of natural products isolated from plant genera Delphinium and Aconitum. Many aconitine alkaloids are found to be potent sodium ion channel modulators. Synthetic studies toward aconitine alkaloids have been ongoing for decades, wherein successful total synthesis has only been accomplished by Wiesner and coworkers thirty years ago. We are in the process of developing a promising convergent strategy to this class of alkaloids. Thus, the synthesis of the complete aconitine skeleton was achieved via a sequence involving N-acyliminium cyclization and radical cyclization. These findings are currently being applied to the total synthesis of 9-deoxylappaconitine.

Analysis of Helix-Mediated Protein-Protein Interactions for Potential Therapeutic Intervention

Andrea Jochim, New York University

This talk will discuss the identity and analysis of helical protein interfaces as potential targets for synthetic modulators of protein–protein interactions. We were inspired in our undertaking by previous studies to determine the number and class of protein drug targets wherein it was determined that less than 400 druggable domains cover all current drug targets—a number that compares poorly with the projected number of protein families. We have assessed the available data on protein–protein complexes with helical interfaces from the Protein Data Bank. Our endeavor has a dual purpose: to provide a dataset for the chemical biology community representing the variety and number of targets available for helix mimetics, and to examine the nature of helices that appear in interface proteins.

A Heritable Mutagenesis System for Directed Evolution Entirely Within Living Cells

Dante Romanini, Columbia University

Directed evolution reigns as the most powerful technique for the generation of biomolecules with new properties and functions, yet its cyclical process of randomization, screening or selection, and amplification of the winning sequences remains labor- and resource-intensive. In contrast to the standard practice of DNA randomization in vitro followed by transformation of the library into a host cell for protein expression, we sought to create a fully in vivo mutagenesis system that would allow for the entire directed evolution cycle to take place within the cell. Specifically, we have developed a method that relies on homologous recombination to introduce cassette-encoded mutations into a gene of interest within yeast cells. The mutagenesis is inducible, proceeds with high efficiency, and is compatible with the sexual reproduction pathway of yeast, allowing desirable sequences to be exchanged among individual members of the cell population. In this way, the most beneficial mutations from very large random libraries can be combined entirely in vivo, without intermediate human manipulation of the coding DNA, to discover proteins with useful new functions.

Discovery of Antibacterial Virulence Inhibitors Targeted at Type III Protein Secretion

Lun K. Tsou, PhD, The Rockefeller University

Type III secretion systems (T3SSs) are used by Gram-negative bacterial pathogens to inject effector proteins into host cells allowing infection and intracellular replication. We developed a two-component enzymatic reporter system generated by fusing caboxy-peptidase G2 (CPG2) to SopE2 effector of Salmonella typhimurium and validated this fusion protein is efficiently secreted via T3SS needle complex. We then screened a collection of 146 Traditional Chinese Medicine extracts and identified potent inhibition of T3SS-dependent secretions of protein effectors. Based on the candidate search from the extracts, we found a novel class of T3SS inhibitors. This class of compounds has the capacity to modulate the secretion of many other Salmonella effectors. Moreover, it also inhibits the infection of salmonella in cells. This study provides a new platform for studying inhibitors of T3SS in Gram-negative bacteria and facilitates the development of new class of antivirulence agents to combat new pathogens.

Exploiting redundancy in the genetic code: control of pathogen virulence via computationally designed genetic material

J. Robert Coleman, PhD, Albert Einstein College of Medicine

The rational design and large-scale de novo synthesis of genetic material makes it possible to customize genes. Given that the genetic code is redundant there is great flexibility in how one can encode a gene at its nucleic acid level without changing the protein it produces. For example, a typical 300 amino acid protein can have up to 10151 encodings, yet the primary amino acid sequence is left unchanged. This flexibility allows for the rational design of the genome of a pathogen to achieve attenuated vaccine strains or antigens that will aid in the development of novel vaccines. Recently, a newly described method of gene manipulation that uses synthetic biology, computer-based gene design and de novo DNA synthesis was used to attenuate viral virulence. The work described herein describes the successful application of genetic manipulation to the problem of bacterial virulence by altering the amount of protein expression, thereby reducing pathogenicity.

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