This site uses cookies.
Learn more.

×

This website uses cookies. Some of the cookies we use are essential for parts of the website to operate while others offer you a better browsing experience. You give us your permission to use cookies, by continuing to use our website after you have received the cookie notification. To find out more about cookies on this website and how to change your cookie settings, see our Privacy policy and Terms of Use.

Natural Products

Natural Products: From Discovery to Therapeutic Applications

Wednesday, March 18, 2020, 8:30 AM - 5:20 PM

The New York Academy of Sciences, 7 World Trade Center, 250 Greenwich St Fl 40, New York

Presented By

The Chemical Biology Discussion Group

The New York Academy of Sciences

 

Naturally occurring compounds have been used medicinally for centuries and continue to be a rich source of novel therapeutics, including antibiotics and cancer drugs. However, it is often challenging to determine the targets of these molecules and elucidate their mechanisms of action. Moreover, detailed understanding of the complex chemistry underlying the biosynthesis of these compounds is critical for functional studies as well as to derive optimized drugs. This one day symposium will discuss the latest research in natural products with a focus on their discovery, mechanisms of action and therapeutic applications across a wide range of disease indications.

Call for Abstracts

Abstract submissions are invited for a poster session. For complete submission instructions, please visit our online portal. The deadline for abstract submission is Wednesday, March 4, 2020.

Registration

Member
By 02/10/2020
$90
After 02/10/2020
$130
Nonmember Academia, Faculty, etc.
By 02/10/2020
$180
After 02/10/2020
$260
Nonmember Corporate, Other
By 02/10/2020
$250
After 02/10/2020
$350
Nonmember Not for Profit
By 02/10/2020
$180
After 02/10/2020
$260
Nonmember Student, Undergrad, Grad, Fellow
By 02/10/2020
$100
After 02/10/2020
$145
Member Student, Post-Doc, Fellow
By 02/10/2020
$50
After 02/10/2020
$70
Earlybird Registration:
0
days
left
Deadline:
14
days
left

Keynote Speaker

Jon Clardy, PhD
Jon Clardy, PhD

Harvard Medical School

Speakers

Rebecca Butcher
Rebecca Butcher, PhD

University of Florida

Emily Balskus, PhD
Emily Balskus, PhD

Harvard University

Peter Senter
Peter Senter, PhD

Seattle Genetics

Steven Townsend
Steven Townsend, PhD

Vanderbilt University

Bo Li, PhD
Bo Li, PhD

University of North Carolina at Chapel Hill

Daniel Nomura
Dan Nomura, PhD

University of California, Berkeley

Elizabeth Sattely
Elizabeth Sattely, PhD

Stanford University

Scientific Organizing Committee

Justin Cisar
Justin Cisar, PhD

Janssen Research & Development

Mo Seyedsayamdost, PhD
Mo Seyedsayamdost, PhD

Princeton University

Derek Tan, PhD
Derek Tan, PhD

Memorial Sloan Kettering Cancer Center

Sara Donnelly, PhD
Sara Donnelly, PhD

The New York Academy of Sciences

Sonya Dougal, PhD
Sonya Dougal, PhD

The New York Academy of Sciences


Wednesday

March 18, 2020

8:30 AM

Breakfast and Registration

9:00 AM

Introduction and Welcome Remarks

Speakers

Sara Donnelly, PhD
The New York Academy of Sciences
Derek Tan, PhD
Memorial Sloan Kettering Cancer Center

Session 1

Session Chairperson
Mo Seyedsayamdost, PhD, University of Princeton
9:15 AM

Keynote Address: Chasing Molecules and Mechanisms in the Gut Microbiome

Speaker

Jon Clardy, PhD
Harvard Medical School

Numerous studies with varying degrees of statistical power have found correlations between the composition of the bacterial population in the human gut microbiome and disease states. But the molecules and mechanism(s) connecting a dysbiotic microbiome to a specific disease are generally unknown. In an attempt to address this gap, we undertook a series of screens to link bacterial metabolites with diseases like type 1 diabetes (T1D) and inflammatory bowel disease (IBD). We focused on primary drivers of inflammation like TNFα (tumor necrosis factor alpha) produced by dendritic cells. The talk will describe our screening logic, the selection of candidate bacterial strains, the discovery of the small molecule regulators of cytokine production, their structures and biosynthesis, and inflammatory mechanism.

10:00 AM

Discovery and Engineering of Plant Chemistry for Plant and Human Health

Speaker

Elizabeth Sattley, PhD
Stanford University

Plants are some of the best chemists on the planet and produce an impressive array of small molecules. We are inspired by the fact that humans have become extraordinarily reliant on plant-derived molecules for food, medicine, and energy. However, remarkably little is known about how plants make these molecules, limiting our ability to engineer and optimize plant metabolic pathways. New plant genome sequences and synthetic biology tools have enabled three research areas under investigation in my lab: 1) Identifying the minimum set of enzymes required to make known plant-derived molecules and non-natural derivatives through metabolic engineering, and 2) discovering new molecules from plants, and 3) developing new strategies to enhance plant fitness. In this talk, I will describe some of our recent efforts to accelerate the discovery of complete plant pathways for known and novel molecules, not only in the model plant Arabidopsis but also in non-model plants.

10:30 AM

Networking Coffee Break

11:00 AM

Human Milk Oligosaccharides and Temporal Development of the Microbiome

Speaker

Steven D. Townsend, PhD
Vanderbilt University
11:30 AM

Chemical Discovery in the Microbial World

Speaker

Emily Balskus, PhD
Harvard University
12:00 PM

Dissecting Chemical Factors from the Gut Microbiota to Improve Cancer Immunotherapy

Speaker

Matthew E. Griffin, PhD
The Rockefeller University

Mounting evidence now suggests that the composition of a patient’s gut microbiota correlates with their response to cancer immunotherapy drugs. However, very little is known about the causative factors that lead to these observations in the clinic. Therefore, determining the chemical basis of these associations would address a key gap in our understanding of host-microbe interactions and may present new avenues to improve outcomes in nonresponsive patients. Here, we present our work to decipher the molecular mechanisms that link the microbial genus Enterococcus with improved patient response to checkpoint blockade. We find that colonization of mice with individual Enterococcus strains and species inhibit cancer growth upon antibody targeting of the PD-1/PD-L1 axis. We then identify an enzymatic factor uniquely produced by active Enterococci. We show that its transfer to an inactive Enterococcus species or the probiotic Lactococcus lactis can phenocopy the anticancer properties of active Enterococci in vivo. Finally, we demonstrate that direct administration of microbial metabolites produced by the enzyme is sufficient to improve checkpoint inhibitor response. Together, these results highlight how specific metabolites from the gut microbiota can alter host response to immunotherapy drugs and reveal a conserved microbial product-host target pathway that may explain clinical observations of Enterococcus colonization in responsive cancer patients.

12:05 PM

A Machine Learning Bioinformatics Tool for Predicting Natural Product Bioactivity

Speaker

Allison Walker, PhD
Harvard Medical School

We developed a machine learning-based bioinformatics tool that predicts natural product bioactivity using the natural product’s biosynthetic gene cluster. We trained three commonly used classifiers, logistic regression, support vector machines, and random forests, on binary classification problems to predict the presence or absence of certain bioactivities. For this initial study we focused on different antimicrobial activities. All classifiers performed well, with balanced accuracies of at least 57% and as high as 79%. Our tool will allow researchers to take advantage of the increasing amount of genetic data to prioritize bacteria that are most likely to produce natural products with desirable activities. We also determined that some biosynthetic genes are highly associated with certain activities, linking molecular features to bioactivity.

12:10 PM

Elucidating the Origin of Preuisolactone A via Biomimetic Synthesis

Speaker

Alexander Novak
New York University

Preuisolactone A is a recently isolated, racemic natural product from the endophytic fungus Preussia isomera. It is marked by a caged structure that contains seven adjacent stereocenters, two of which are quarternary. Biosynthetically, preuisolactone A was proposed to be formed via the terpene pathway featuring several oxidative editing steps. We propose an alternative biosynthetic hypothesis and have completed a short, biomimetic synthesis that follows our proposal. Its features are a purpurogallin-type [5+2]-cycloaddition, followed by a retro-Dieckmann reaction, vinylogous aldol addition, oxidative lactonization and a final, unprecedented benzilic acid rearrangement. The synthesis furnished preuisolactone A in essentially three steps in high overall yield. Our work explains why preuisolactone A has been isolated as a racemate and suggests that it is not a terpenoid but a phenolic polyketide.

12:15 PM

Networking Lunch and Poster Session

Speakers

Odd number posters: 12:45pm - 1:15pm
Even number posters: 1:15pm - 1:45pm

Session 2

Session Chairperson
Justin Cisar, PhD, Janssen Research & Development
1:45 PM

Reimagining Druggability Using Chemoproteomic Platforms

Speaker

Dan Nomura, PhD
University of California, Berkeley

The Nomura Research Group is focused on redefining druggability using chemoproteomic platforms to develop transformative medicines. One of the greatest challenges that we face in discovering new disease therapies is that most proteins are considered “undruggable,” in that most proteins do not possess known binding pockets or “druggable hotspots” that small-molecules can bind to modulate protein function. Our research group addresses this challenge by advancing and applying chemoproteomic platforms to discover and pharmacologically target unique and novel druggable hotspots for disease therapy. We currently have three major research directions. Our first major focus is on developing and applying chemoproteomics-enabled covalent ligand discovery approaches to rapidly discover small-molecule therapeutic leads that target unique and novel druggable hotspots for undruggable protein targets and pathways. Our second research area focuses on discovering and exploiting unique druggable modalities accessed by natural products. Our third research area focuses on using chemoproteomics-enabled covalent ligand discovery platforms to expand the scope of targeted protein degradation and to discover new induced proximity-based therapeutic modalities.Collectively, our lab is focused on developing next-generation transformative medicines through pioneering innovative chemical technologies to overcome challenges in drug discovery.

2:15 PM

Decoding the Chemical Signals of the Worm

Speaker

Rebecca Butcher, PhD
University of Florida

The nemamides are produced by two megaenzymes, PKS-1 and NRPS-1, in two essential neurons in the nematode C. elegans and promote survival of the worm during starvation.  These natural products are quite remarkable as they represent the first hybrid polyketide-nonribosomal peptides to be discovered in an animal species.  Our lab is studying how the biosynthesis of these natural products is coordinated in the context of a complex animal system in order to influence underlying physiology.  We have used CRISPR-Cas9 to sequentially inactivate enzymatic domains in PKS-1 and NRPS-1 in order to map the assembly-line process that leads to the nemamides.  Furthermore, we have identified multiple additional enzymes, encoded by genes distributed throughout the genome, that function in trans in nemamide biosynthesis.   Our work reveals a number of noncanonical features to nemamide biosynthesis, provides new insights into the trafficking of biosynthetic intermediates, and shows how nemamide production is coupled to the production of other signaling molecules in the worm.

2:45 PM

Networking Coffee Break

3:15 PM

Mighty Chemistry of Bacterial Small Molecules as Antibiotics

Speaker

Bo Li, PhD
University of North Carolina at Chapel Hill

Bacteria produce many small molecules that possess unique structures and potent antimicrobialactivity. It is often unclear how these molecules impart their activity. I will discuss our work on understanding the mode of action for the broad-spectrum, dithiolopyrrolone antibiotics. We showed that this family of natural products inhibits metal-dependent enzymes in cells via metal-ion chelation. The cyclic ene-disulfide of the dithiolopyrrolone exhibits unusual redox chemistry and is essential for activity. I will also describe our efforts on elucidating the mode of action of the natural product thiomarinol A. Thiomarinol A is a hybrid antibiotic that combines the dithiolopyrrolone and a close analog of mupirocin, the latter of which is used to treat methicillin-resistant Staphylococcus aureus. Our work identified novel antimicrobial mechanisms and could help discover and design antibiotics that can avoid or overcome resistance.

3:45 PM

Potent Antibody-Based Conjugates for Cancer Therapy: From Early Stage Research to a Clinically Approved Drug

Speaker

Peter Senter, PhD
Seattle Genetics
4:15 PM

Closing Remarks

Speaker

Justin Cisar, PhD
Janssen Research & Development
4:20 PM

Networking Reception

5:20 PM

Adjourn