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VICB 2015 Fall Seminar Schedule

 

 

Rami Hannoush

Genentech - Stanford University School of Medicine

 

"Challenging Targets and Emerging Approaches for Cellular Imaging in the Wnt Pathway" 

 

Wednesday, September 2, 2015

12:15 P.M. — 1:15 P.M.

1220 MRB III

 

Key Lecture Points:
· The Wnt signaling pathway in cancer
· Strategies for targeting the Wnt pathway
· Imaging approaches of lipidated Wnt ligands
· Trafficking and secretion of Wnt ligands
· Biochemistry and enzymology of Wnt fatty acyl transferases

 

Nicholas Meanwell

Bristol-myers squibb

 

"Inhibitors of Hepatitis C Virus For Use in Combination Therapy: Asunaprevir, Daclatasvir and NS5A Synergists" 

 

Wednesday, September 9, 2015

12:15 P.M. — 1:15 P.M.

1220 MRB III

 

Key Lecture Points:
· Hepatitis C virus chronically infects approximately 200 million individuals worldwide.

· High viral replication rates and an error-prone polymerase contribute to virus diversity (7 genotypes, 67 subtypes) and the emergence of resistance to drug monotherapy, anticipating combination therapy.

· Until 2011, therapy comprised of a combination of sub-cutaneous pegylated interferon-α and ribavirin for 48 weeks with cure rates of ~50% for the most difficult genotype, genotype 1.

· In 2011 the first direct-acting antiviral agents, the NS3 protease inhibitors telaprevir and boceprevir were introduced as add-on therapy.

· In 2014, the first direct-acting antiviral drug combinations were introduced in Japan and the US with cure rates of >85% after 8-24 weeks of therapy.

· The discovery of the cyclopropyl acylsulfonamide moiety, a key structural element in many clinically evaluated and approved NS3 protease inhibitors, will be described in the context of the identification of asunaprevir.

· The development and implementation of a phenotypic screen designed to identify novel HCV inhibitors that led to the discovery of the first-in-class NS5A inhibitor daclatasvir will be described. NS5A is a protein with no known enzymatic activity that plays a key role in virus replication and assembly and inhibitors of NS5A are the most potent HCV inhibitors known to date with pico-molar EC50 values in cell culture.

· The discovery of NS5A synergists that can restore the sensitivity of daclatasvir-resistant virus to wild type levels will be discussed.

·The current state of the clinical efficacy with direct-acting antiviral agents will be summarized.

Laura Bohn

The Scripps Research Institute

 

"Ligand-Directing Opioid Receptor Signaling to Promote Analgesia and Avoid Side Effects"

 

Wednesday, September 16, 2015

12:15 P.M. — 1:15 P.M.

1220 MRB III

 

Key Lecture Points:
· Mu and Kappa opioid receptors as analgesic targets
· Diverse G protein coupled receptor signaling promoted by different agonists
· Optimizing drug discovery efforts to engage different signaling pathways downstream of receptors
· Elucidation of desirable and undesirable signaling pathways to preserve efficacy and avoid side effects using pharmacological and genetic means.

Gunda Georg

University of Minnesota

 

"Recent Progress in Male Contraception"

 

Wednesday, September 23, 2015

12:15 P.M. — 1:15 P.M.

1220 MRB III

 

Key Lecture Points:
· Introduction to contraception
· The male reproductive system
· Targets for male contraception
· Discovery of gamendazole for male contraception
· Preclinical development of gamendazole
· Progress towards the discovery of BRDT inhibitors

Taekjip Ha

Johns hopkins university

 

"Surprising Physics of DNA on the Genome Scale"

 

Wednesday, September 30, 2015

12:15 P.M. — 1:15 P.M.

1220 MRB III

 

Key Lecture Points:

· Single molecule assay for DNA flexibility
· fluorescence-force spectroscopy reveals nucleosome unravels asymmetrically under tension
· Nucleosome mechanical stability is controlled by DNA flexibility
· Loop-seq for genome-wide mapping of DNA flexibility

Carl Nathan   

Weill Cornell Medical College

 

"Killing Persistent Mycobacterium tuberculosis" 

 

Wednesday, October 7, 2015

12:15 P.M. — 1:15 P.M.

1220 MRB III

 

Key Lecture Points:
· Antimicrobial resistance (AMR) is a major medical problem. Tuberculosis is probably the most prevalent example of AMR and the single leading cause of death from bacterial infection.
· Host immunity can put Mycobacterium tuberculosis (Mtb) into a state of phenotypic resistance to conventional anti-infectives. Phenotypic drug resistance is an even bigger problem in TB than heritable drug resistance.
· We are seeking drugs that can kill phenotypically resistant Mtb.
· One novel approach is to inhibit, not protein synthesis, but protein breakdown. We identified the first agents that can inhibit the proteasome of a pathogen while sparing the proteasome of its host.

 

 

Helen Blackwell

University of Wisconsin, Madison

 

"Expanding the Language of Bacterial Communication Using Synthetic Ligands" 

 

Wednesday, October 14, 2015

12:15 P.M. — 1:15 P.M.

1220 MRB III

 

Key Lecture Points:
· Introduction to quorum sensing in bacteria
· How can chemical tools be used to interrogate bacterial quorum sensing?
· Our recent development of chemical inhibitors and activators of quorum sensing:
in Gram negative pathogens

in Gram-positive pathogens

· Application of chemical tools to study quorum sensing in infection and its role in interspecies interactions
· Integration of these agents into polymer films for virulence/biofilm control

David Sherman

University of Michigan

 

"Engineering Biocatalysis for Creation of Novel Natural Products" 

 

Wednesday, October 21, 2015

12:15 P.M. — 1:15 P.M.

1220 MRB III

 

Key Lecture Points:
· Natural Product Molecules are Experiencing a Resurgent Interest in Drug Discovery Programs
· Microbiomes from Diverse Habitats are Providing a Wealth of New Diversity in Secondary Metabolism
· Bioinformatic Tools are Enabling Access to New Genomes and Pathways for Natural Product Discovery
· Engineering Biosynthetic Enzymes and Pathways are Providing Access to New Bioactive Metabolites
· Developing New Disease Targets is Allowing Unique Access to Novel Natural Product Structures

Michelle Arkin

University of california, San Francisco

 

"Drug Discovery Challenges, Large and Small" 

 

Wednesday, October 28, 2015

12:15 P.M. — 1:15 P.M.

1220 MRB III

 

Key Lecture Points:
· Our lab develops small-molecule probes and novel assays to address challenging problems in drug discovery
· This seminar will provide two diverse examples from neurodegeneration and parasitology
· Caspase-6 is a cysteine protease implicated in Alzheimer’s Disease, and is activated in cells bearing a neurotoxic form of the protein tau
· Three different screens for caspase-6 inhibitors yielded molecules with three mechanisms of action
· The round worm Schistosoma, the causative agent of Schistosomiasis, has a complex lifecycle
· We have developed a high-throughput, time-lapsed imaging method to quantify Schistosoma response to drugs and other perturbogens

Nathanael Gray

Dana-Farber Cancer Institute

 

"Targeting Cancer with Covalent Inhibitors"  

 

Wednesday, November 4, 2015

12:15 P.M. — 1:15 P.M.

1220 MRB III

 

Key Lecture Points:
· Overview of kinase inhibitors for treatment of cancer
· CDK7 inhibitors for transcriptional therapy
· Her3 pseudo kinase binders
· CDK12 inhibitors
· KRAS inhibitors

John Hepler

Emory University

 

"RGS14 at the Interface of Hippocampal Signaling and Synaptic Plasticity" 

 

Wednesday, November 11, 2015

12:15 P.M. — 1:15 P.M.

1220 MRB III

 

Key Lecture Points:
· RGS14 is a multifunctional signaling protein that binds G proteins (Gai) and active H-Ras-GTP
· RGS14 is expressed almost exclusively in dendrites and spines of neurons in hippocampal area CA2
· Knock-out of the RGS14 gene/protein results in mice that learn faster and remember better
· Loss of RGS14 also results in nascent long-term potentiation (LTP) and synaptic plasticity in CA2 neurons where it is otherwise absent
· Synaptic plasticity and LTP is regulated by both Ca++ (Calmodulin (CaM), CaMKII) and ERK signaling
· At the cellular level, RGS14 binds inactive Gai-GDP which anchors it at the plasma membrane
· RGS14 also binds active H-Ras-GTP, and binding of H-Ras inhibits stimulated ERK signaling
· RGS14 also binds Ca++ activated Calmodulin (Ca++/CaM) and is phosphorylated by CaMKII
· The Gai1:RGS14 signaling complex is regulated by Gi-linked GPCRs
· A model if proposed whereby RGS14 integrates G protein, H-Ras/ERK and Ca++/CaM signaling pathways to regulate synaptic signaling, plasticity, and hippocampal learning and memory

John Porco

Boston University

 

"Recent Studies Towards The Synthesis of Tetrahydroxanthone Natural Products"  

 

Wednesday, November 18, 2015

12:15 P.M. — 1:15 P.M.

1220 MRB III

 

Key Lecture Points:
· A concise approach to additional tetrahydroxanthone natural products employing vinylogous addition of siloxyfurans to benzopyryliums derived from chromones and a late-stage Dieckmann cyclization has also developed (1)

· The methodology led to development of efficient syntheses of the antitumor agents secalonic acids A and D (2) . . .

· as well as a seven-step atropselective total synthesis of the dimeric tetrahydroxanthone antibioticrugulotrosin A (3).

 

(1) Vinylogous Addition of Siloxyfurans to Benzopyryliums: A Concise Approach to the Tetrahydroxanthone Natural Products. Qin, T.; Johnson, R. P.; and Porco, J.A. Jr. J. Am. Chem. Soc. 2011, 133, 1714–1717.
(2) Total Syntheses of Secalonic Acids A and D. Qin, T.; Porco, J.A. Jr. Angew. Chem. Int. Ed. Engl., 2014, 53, 3107-3110.

(3) Atropselective Syntheses of (-) and (+) Rugulotrosin A Utilizing Point-to-Axial Chirality Transfer. Qin, T.; Skraba-Joiner, S.L.; Khalil, Z.G.; Johnson, R.P.; Capon, R.J.; Porco J.A, Jr. Nat. Chem. 2015, 7, 234-40.

 

Richard DiMarchi

Indiana University

 

"Peptide-Based Therapeutics: From Hormones to Polypharmacy" 

 

Wednesday, December 2, 2015

12:15 P.M. — 1:15 P.M.

1220 MRB III

 

Key Lecture Points:
· Evolution of macromolecule drug synthesis
· Recruitment of glucagon agonism to treat metabolic diseases
· Overlapping, but unique properties of GIP & GLP
· Preparation of triple agonists and application of lipidation of a medicinal tool
· Molecular basis for mixed incretin agonism & antagonism.

Mark Brown

Cleveland Clinic

 

"Gut Microbial Metabolites as Metaorganismal Hormones Regulating Host Energy Metabolism"  

 

Wednesday, December 9, 2015

12:15 P.M. — 1:15 P.M.

1220 MRB III

 

Key Lecture Points:
· Resident microbial communities and host collectively create a metaorganism that promotes metabolism of nutrients that influence susceptibility for the development of CVD.

· Intestinal microbiota-dependent metabolism of phosphatidylcholine and L-carnitine produces trimethylamine (TMA), which is further metabolized by the host enzyme Flavin Monooxygenase 3 (FMO3) to the proatherogenic compound trimethylamine-N-oxide (TMAO).

· Both TMA and TMAO exhibit properties that are "hormone-like" in nature, and the postprandial generation of the gut microbe-derived hormones impact metabolic disease in the host.

Dirk Trauner

Ludwig Maximilian University of Munich

 

"Controlling Biological Function with Photopharmacology”

 

Wednesday, December 16, 2015

12:15 P.M. — 1:15 P.M.

1220 MRB III

 

Key Lecture Points:

· Few types natural photoswitches are involved in photobiology (incl. human vision).

· Chemists have come up with numerous synthetic photoswitches.

· We have attached those to naturally “blind” proteins to control them with light (“Photopharmacology”).

· We can regulate ion channels, GPCRs, transporters and RTKs in such a way.

· The cytoskeleton can also be precisely controlled with Photopharmacology.

· So can lipids.

· As such, Photopharmacology can be used to restore vision, fight cancer, and alleviate pain.

 

Winter - Spring 2016
Seminar Schedule

 

 


Howard Hang

Rockefeller University

 

"Chemical Reporters for Exploring Posttranslational Modifications" 

 

Wednesday, January 13, 2016

12:15 P.M. — 1:15 P.M.

1220 MRB III

 

Key Lecture Points:

· Chemical reporters enable sensitive detection and enrichment of protein modifications
· New methods for identifying and quantifying S-fatty-acylated proteins
· Discovery and functional analysis S-palmitoylated interferon-effectors (IFITMs)
· Pathogen targeting of protein fatty-acylation during infection

Joe Lutkenhaus

University of Kansas

 

"Regulation of Bacterial Cell Division" 

 

Wednesday, January 20, 2016

12:15 P.M. — 1:15 P.M.

1220 MRB III

 

Research Overview:

· Elucidating the molecular machinery responsible for cell division in bacteria and
· Determination of the temporal and spatial regulatory mechanisms necessary to ensure that the septum is placed at midcell and that newborn cells each receive a copy of the chromosome
· Our work with the bacterium E. coli has led to the discovery of a cytoskeletel element, the Z ring, that directs septation in all prokaryotic organisms. The Z ring is formed by the self assembly of FtsZ, the ancestral homologue of tubulin.

Alexander Deiters

University of Pittsburgh

 

"Optical Control of Cellular Processes"  

 

Wednesday, January 27, 2016

12:15 P.M. — 1:15 P.M.

1220 MRB III

 

Key Lecture Points:

· Caged proteins
· Caged nucleic acids
· Unnatural amino acid mutagenesis
· Regulation of gene expression
· Regulation of protein function

 

Priscilla Yang

Harvard

 

"Host Pathogen Interactions and Opportunities for New Antivirals"

 

Wednesday, February 3, 2016

12:15 P.M. — 1:15 P.M.

1220 MRB III

 

Key Lecture Points:

· We lack effective countermeasures against most viral pathogens

· There is a need for alternative strategies to combat emerging and re-emerging viral pathogens

· in particular, agents with naturally high barriers to resistance and multispectrum activity

· Chemical biology provides tools to probe basic molecular mechanisms underlying viral processes and to discover and validate novel antiviral targets

· Discovery of kinase inhibitors and a bioactive lipid that block dengue virus genome replication

· Opportunities to examine if host-targeted antivirals have multispectrum activity against families of virus and high barriers to antiviral resistance

· Serendipitous discovery that allosteric Abl kinase inhibitor GNF2 also inhibits the dengue virus E protein

· Development of Dengue E inhibitors to pharmacologically validate E as an antiviral target

· Viruses use host membranes as platforms for gene expression, genome replication, and assembly. We have used LC-MS-based lipidomic profiling to explore the hypotheses that viruses utilize membranes with lipid composition optimized for their function and have evolved mechanisms to alter steady-state lipid metabolism in ways that increase the availability of the specific lipids needed for efficient viral replication.

Min Chen

University of massachusetts

 

"Outer Membrane Protein G and Its Application in Biotechnology"

 

Wednesday, February 10, 2016

12:15 P.M. — 1:15 P.M.

1220 MRB III

 

Key Lecture Points:

· The dynamic movement of outer membrane protein G (OmpG) nanopore can be harnessed to distinguish protein homologues and isoforms in complex mixture.
· Electrostatic interaction between OmpG loops and the analyte proteins contributes to the high-selectivity of OmpG nanopore sensor.
· Gating of OmpG is controlled by the repulsion force between the loops.
· OmpG sensor array improves the detection selectivity.

 

Rebecca Butcher

University of Florida

 

"Structure, Biosynthesis, and Mechanism of Small-Molecule Signals Controlling Nematode Development"  

 

Wednesday, February 17, 2016

12:15 P.M. — 1:15 P.M.

1220 MRB III

 

Key Lecture Points:

· Ascarosides serve as pheromones controlling nematode development, physiology, and behavior
· Role of acyl-CoA oxidases in ascaroside biosynthesis
· Structural basis for acyl-CoA oxidase substrate specificity
· Effect of environmental conditions on the ascaroside biosynthetic pathway
· Identification of structurally novel small-molecule signals controlling nematode development and their mechanism of action.

 

John MacMillan

UT - Southwestern

 

"Information Rich Screening to Identify Natural Product Scaffolds"  

 

Wednesday, February 24, 2016

12:15 P.M. — 1:15 P.M.

1220 MRB III

 

Key Lecture Points:

· Natural Product discovery

· Phenotypic screening and mechanism of action

· Selective toxins for non-small cell lung cancer

· Hypoxia inducible factor inhibitors

Louis-Charles Campeau

Merck

 

"Discovery and Development of Novel Catalytic Reactions in the Manufacturing of an Active Pharmaceutical Ingredient of ZEPATIER™"  

 

Wednesday, March 2, 2016

12:15 P.M. — 1:15 P.M.

1220 MRB III

 

Key Lecture Points:

· The role that Merck Chemistry plays in the discovery & development of novel therapies.

· What do Process Chemists do in the development of an ideal manufacturing route?

· Zepatier and the chemistry of Elbasvir.
· Development of novel catalytic reactions in the development of manufacturing processes.
· An improved, greener, manufacturing process for Elbasvir.

Dale Boger

Scripps Research Institute

 

"Redesign of Vancomycin for Resistant Bacteria"

 

Wednesday, March 16, 2016

12:15 P.M. — 1:15 P.M.

1220 MRB III

 

Key Lecture Points:

· A summary of studies on the total synthesis and evaluation of the vancomycin family of glycopeptides antibiotics their ligand binding pocket redesign to address the underlying molecular basis of resistance their subsequent peripheral tailoring to address the emerging public health problem of vancomycin resistance will be presented.

Sean Brady

Rockefeller University

 

"Watch Your Step, There is New Chemistry Everywhere"   

 

Wednesday, March 23, 2016

12:15 P.M. — 1:15 P.M.

1220 MRB III

 

Key Lecture Points:

· Traditional culture-based approaches used for the discovery of natural products only provide access to a small fraction of the biosynthetic diversity present in nature.

· Uncultivated microorganisms are an attractive source of potentially new natural products.

· I will present work resulting from the culture independent investigation of soil and human microbiomes for new bioactive natural products.

Richard Cerione

Cornell University

 

"New Ways to Think About Rho GTPase-Signaling: A Continual Evolving Journey"

 

Wednesday, April 6, 2016

12:15 P.M. — 1:15 P.M.

1220 MRB III

 

Key Lecture Points:

· Rho GTPases signal to cellular metabolism machinery ·
· Glutaminase C is a key node in cancer cell metabolism
· Microvesicles are generated in cancer cells as an outcome of Rho GTPase-signaling and metabolic re-programming
· Targeting microvesicles offers new strategies for therapeutic intervention.

Meg Phillips

UT Southwestern

 

"Targeting Malaria Dihydroorotate Dehydrogenase"  

 

Wednesday, April 13, 2016

12:15 P.M. — 1:15 P.M.

1220 MRB III

 

Key Lecture Points:

Malaria the disease:

· pyrimidine biosynthetic pathway
· dihydroorotate dehydrogenase (DHODH) as a drug target
· identifying inhibitors of DHODH for malaria drug discovery
· progressing DHODH inhibitors to identify a clinical candidate

Emil Alexov

Clemson University

 

"Revealing Molecular Mechanism of Mono-genetic Disorders and Targeting the Disease-Causing Effect with Small Molecules"  

 

Wednesday, April 20, 2016

12:15 P.M. — 1:15 P.M.

1220 MRB III

 

Key Lecture Points:

· Disease-causing amino acid mutations affect biophysical properties of the corresponding protein
· Frequently mutations do not completely abolish protein function
· Frequently mutation sites are accessible from the water phase
· Frequently disease-causing mutations do not affect the active site of the corresponding gprotein
· Small molecules (potential drugs) can be designed to binding to malfunctioning protein and restore wild type activity

David Liu

Harvard University

 

"Integrating Chemistry and Evolution to Illuminate Biology and Enable Next-Generation Therapeutics"

 

Wednesday, April 27, 2016

12:15 P.M. — 1:15 P.M.

1220 MRB III

 

Lecture Overview:

In this lecture I will describe two areas of research in our laboratory that integrate chemistry with the principles underlying biological evolution to illuminate biology and enable next-generation therapeutics. The first area uses DNA-templated synthesis, a method to translate DNA sequences into synthetic molecules, coupled with in vitro selection, to discover small-molecule macrocycles that are capable of modulating the activity of therapeutically relevant proteins. Recent discoveries from this effort include the first physiologically active inhibitor of insulin-degrading enzyme (IDE), which we used in collaboration with Professor Alan Saghatelian to validate the potential of IDE as a new therapeutic target for the treatment of diabetes and to discover new biological functions of IDE in regulating glucose homeostasis.


The second area of research has led to the development of phage-assisted continuous evolution (PACE), a method that enables proteins to evolve continuously in the laboratory for the first time. We have used PACE to rapidly evolve a wide variety of proteins, several of which have potential to serve as novel therapeutic agents. We have also used PACE to characterize the reproducibility and path dependence of long evolutionary trajectories, and to reveal the molecular basis of evolutionary stochasticity and path dependence for T7 RNA polymerase. Finally, I will describe a new effort that uses PACE to overcome a major problem facing worldwide agricultural productivity: the rise of insects resistant to a widely used genetic insecticide.

 

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The Vanderbilt Institute of Chemical Biology, 896 Preston Building, Nashville, TN 37232-6304, phone 866.303 VICB (8422), fax 615 936 3884
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