Targeting RNA Using Small Molecules

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Targeting RNA Using Small Molecules

Tuesday, September 26, 2017

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

Presented By

Biochemical Pharmacology Discussion Group

The New York Academy of Sciences


Recent advances in our understanding of the structure and function of RNA has opened up a wealth of putative therapeutic targets, greatly enriching drug discovery research programs. Nonetheless, the ability to selectively target RNA remains difficult, hampered by both the screening tools available and by our limited understanding of RNA-small molecule interactions.

This symposium will explore leading edge research on RNA dynamics covering currently available assays, detection tools, and imaging platforms, while also providing an in-depth discussion of recent advances for studying RNA function, and ultimately targeting RNA for treating and curing disease.

Call for Abstracts

Abstract submissions are invited for a poster session, and two abstracts will be selected for short talks. For complete submission instructions, please visit our online portal. The deadline for abstract submission is August 11, 2017.


Nonmember Academia, Faculty, etc.
Nonmember Corporate, Other
Nonmember Not for Profit
Nonmember Student, Undergrad, Grad, Fellow
Member Student, Post-Doc, Fellow
Nonmember Academia, Faculty, etc.
Nonmember Corporate, Other
Nonmember Not for Profit
Nonmember Student, Undergrad, Grad, Fellow
Member Student, Post-Doc, Fellow


Targeting RNA Using Small Molecules
Samuel Hasson, PhD, Pfizer
Targeting RNA Using Small Molecules
Lyn Jones, PhD, Jnana Therapeutics
Targeting RNA Using Small Molecules
Martin Pettersson, PhD, Pfizer
Targeting RNA Using Small Molecules
Claire Steppan, PhD, Pfizer
Targeting RNA Using Small Molecules
Erick Young, PhD, Boehringer Ingelheim
Targeting RNA Using Small Molecules
Sonya Dougal, PhD, The New York Academy of Sciences
Targeting RNA Using Small Molecules
Caitlin McOmish, PhD, The New York Academy of Sciences


Targeting RNA Using Small Molecules
Nathan J. Baird, PhD, University of Sciences
Targeting RNA Using Small Molecules
Matthew D. Disney, PhD, Scripps Research Institute
Targeting RNA Using Small Molecules
John A. Howe, PhD, Merck Research Laboratories
Targeting RNA Using Small Molecules
Amanda L. Garner, PhD, University of Michigan
Targeting RNA Using Small Molecules
David H. Mathews, MD, PhD, University of Rochester
Targeting RNA Using Small Molecules
Kevin M. Weeks, PhD, University of North Carolina at Chapel Hill
Targeting RNA Using Small Molecules
Steven C. Zimmerman, PhD, University of Illinois


The Biochemical Pharmacology Discussion Group is proudly supported by:


ACS New York Section

Vertex Pharmaceuticals Inc

This program is supported by an educational grant from


Premiere Supporter

Academy Friend

Arrakis Therapeutics


September 26, 2017

8:30 AM

Breakfast and Registration

9:00 AM

Introduction and Welcome Remarks


Sonya Dougal, PhD
The New York Academy of Sciences
Samuel Hasson, PhD

Session 1

9:15 AM

A Pervasive Role for Structure in lncRNA and mRNA Function


Kevin M. Weeks, PhD
University of North Carolina at Chapel Hill

The functions of many RNA molecules – including mRNAs, long non-coding RNAs, and the genomes of RNA viruses – require that an RNA fold back on itself to create intricately and complexly folded structures. Until recently, however, we had little idea of the broad interrelationships between RNA structure and function because there simply did not exist chemical tools for rigorously examining the structures of RNA molecules in cells and viruses. In addition, if it were possible to reliably and robustly identify sites with function-related structures in large RNAs, such discoveries would open up new opportunities for therapeutic targeting of RNA using small molecules. This talk will focus on recent progress in our lab with high-resolution RNA structure probing over large scales such that both secondary and tertiary structure elements can be identified and such that these structural data can be used to identify RNA elements likely to have direct and important roles in cellular function and gene regulation.

9:45 AM

Modeling RNA Secondary Structure to Identify Targets


David H. Mathews, MD, PhD
University of Rochester Medical Center

RNA secondary structure can be predicted using folding thermodynamics. Free energy minimization is commonly used to predict structures, but it only predicts about 70% of base pairs on average. Our group develops methods to improve the accuracy of structure prediction, including methods to estimate Boltzmann probabilities of structures, methods to predict conserved structures in multiple homologs, and methods to use experimental mapping data to improve modeling accuracy.

In this talk, I’ll present three new approaches we developed for RNA secondary structure prediction. We recently demonstrated that estimating the probability of loop formation can predict loops with higher fidelity than free energy minimization. We also developed a new method, called Rsample, to use SHAPE mapping data to model the structures of RNAs that fold to multiple structures. We can accurately model the structures, and also their population. Finally, we advanced our TurboFold method to predict conserved structures across multiple sequences. TurboFold now estimates multiple sequence alignments. It can also use SHAPE data for one or more homologs to improve the accuracy of structure prediction.

These methods are freely available in the RNAstructure software package, which can be downloaded at .

10:15 AM

Networking Coffee Break

10:45 AM

Sequenced-based Design of Precise Small Molecules Targeting RNA: Novel Approaches


Matthew D. Disney, PhD
Scripps Research Institute

RNA has been a long sought-after target for small molecules.  Three-dimensionally folded RNAs such as the bacterial ribosome and riboswitches are well known and validated targets for small molecules.  Human RNAs that contribute to disease, however, have been recalcitrant to small molecule targeting.  Our group has developed multiple approaches to efficiently deliver lead bioactive small molecules targeting RNA over the past dozen years.  Our non-traditional lead identification strategy uses selection-based approaches to assign affinity landscapes for the RNA motifs that are bound by small molecules.  These landscapes are defined by using a novel library-versus-library screening approach named Two-Dimensional Combinatorial Screening (2DCS), which probes libraries of small molecules for binding to libraries of RNA motifs simultaneously.  Although not highly regarded in its infancy, the developments of 2DCS and a computational approach dubbed Inforna that identifies druggable motifs derived from 2DCS in human RNAs, has delivered a myriad of lead small molecules that inhibit many human disease-causing RNAs in cellular and animal disease models.  Targets to which bioactive compounds have been delivered include RNA repeating transcripts that cause genetically-defined rare diseases and non-coding RNAs that cause cancer.  In this talk, I will describe the history of these approaches and also a first-class approach to validate the targets of small molecules, Chemical Cross-Linking and Isolation by Pull Down (Chem-CLIP).  Chem-CLIP has also defined rules for drugging non-coding RNAs, particularly microRNA precursors, that contribute to a myriad of diseases.  These studies have laid a foundation to rationally design small molecules targeting RNA by using non-traditional approaches and have delivered multiple bioactive compounds for diseases to which there are no known cures or that have poor prognoses.

11:15 AM

A Diversity of RNA Conformations, a Profusion of Putative Targets, and a Multi - dimensional Approach to Make Sense of It All


Nathan J. Baird, PhD
University of the Sciences

Given the demonstrated importance and therapeutic potential of RNA biology in human health and disease, the dearth of studies aimed at targeting structured RNAs with small molecules is alarming. RNA remains a disproportionately under-explored target for drug discovery owing in part to the limited number of protein-centric assays currently employed for the discovery of new small molecules targeting RNA. Effective RNA-centric assays should instead account for the propensity of RNA to adopt alternative, non-functional conformers. These conformers present distinct binding sites which, when occupied with a small molecule, may preclude formation of the native structure. Yet high-throughput assays designed to explore RNA conformational space are not common.

We hypothesize that targeting the RNA folding process, in lieu of simple RNA binding analysis, will more thoroughly assess the ‘druggability’ of structured RNA targets of interest. We developed an efficient, high-throughput method to simultaneously screen chemical libraries and RNA structural space to discover novel chemical modulators of RNA structure and function. Using Förster resonance energy transfer (FRET), we generate multi-dimensional landscapes characterizing RNA conformations and thermodynamic stability. To demonstrate the utility of this approach we investigated landscapes of the cyclic di-GMP riboswitch in response to Mg2+, small molecule, and temperature. Our landscape analysis uncovers an otherwise hidden RNA-small molecule interaction that inhibits the function of this RNA through stabilization of a non-native conformation. Hence, targeting alternate conformers is a viable approach to discover new RNA-ligand interactions, highlighting how biophysics informs biology and therapeutic design.

11:45 AM

Compounds Targeting HIV-1 Frameshift RNA Demonstrate Antiviral Activity against HIV in Human Cells


Viktoriya Anokhina, MSc
University of Rochester

According to World Health Organization, there were approximately 36.7 million people living with HIV at the end of 2015. Despite the success of combination antiretroviral therapy (cART), HIV/AIDS remains one of the world's most significant public health challenges. Ongoing challenges associated with HIV/AIDS include the complex regimen of antiretroviral therapy, cardiovascular and neurological complications associated with cART, and viral ability to require resistance due to high mutation rates. These issues require exploration of new viral targets and development of other therapies. HIV relies on a -1 ribosomal frameshift for the production of several essential viral proteins. This process is regulated by the HIV-1 Frameshifting Stimulatory Signal(FSS), a highly conserved 22 nt stemloop located downstream to a UUUUUUA “slippery sequence” that is also required for -1 ribosomal event to occur. There is a large body of evidence suggesting that targeting the HIV-1 FSS could be of therapeutic value. Since the HIV-1 FSS RNA contains a unique sequence with an extremely stable hairpin structure, we hypothesized that frameshifting can be targeted specifically without affecting normal cell physiology. Here, we synthetized and evaluated triazole-containing analogs of a hit compound determined previously via Dynamic Combinatorial Selection. Compounds demonstrated strong binding selectivity for the HIV-1 FSS, and antiviral activity against HIV in human cells including a highly cytopathic, multi-drug resistant strain.

11:55 AM

Deciphering Patterns in Selective Small Molecule:RNA Interactions


Amanda E. Hargrove, PhD
Duke University

While small molecules offer a unique opportunity to target structural and regulatory elements in therapeutically relevant RNA, selectivity has been a recurrent challenge in small molecule: RNA recognition. In particular, RNAs tend to be more dynamic and offer less chemical functionality than proteins, and biologically active ligands must compete with the highly abundant and highly structured RNA of the ribosome. Indeed, no small molecule drugs targeting RNAs other than the ribosome are currently available, and our recent survey of the literature revealed little more than one hundred reported chemical probes that target non-ribosomal RNA in biological systems. As part of our efforts to improve small molecule targeting strategies and gain fundamental insights into small molecule:RNA recognition, we are analyzing patterns in both RNA-biased small molecule chemical space and RNA topological space privileged for differentiation. To begin, we identified physicochemical, structural, and spatial properties properties of biologically active RNA ligands that are distinct from those of protein-targeted ligands. Elaboration of four RNA binding scaffolds into a library enriched with these properties has led to improved recognition of medicinally relevant RNA targets. At the same time, we used pattern recognition protocols to identify RNA topologies that can be differentially recognized by small molecules. We are currently expanding these studies with the ultimate goal of applying these insights to the rapid development of ligands with high affinity and specificity for a wide range of RNA targets, particularly those critical to cancer progression.

12:05 PM

Networking Lunch and Poster Viewing

Session 2

1:30 PM

New Strategies for Developing Small and Large Molecules that Target the DNA and RNA Causing Disease


Steven C. Zimmerman, PhD
University of Illinois at Urbana-Champaign

Only about 2% of the human genome codes for proteins yet 90% is transcribed to RNA. This RNA has become a prime target for the development of new therapeutic agents. For example, the RNA trinucleotide repeat sequence (CUG)n is believed to be the primary cause of myotonic dystrophy type 1 (DM1) an incurable neuromuscular disease afftecting about 1 in 8000 people. The rational design of small molecules targeting this sequence can be accomplished using simple principles of supramolecular chemistry combined with known ligands that bind oligonucleotides. Polyvalent drug design allows for increasing affinity and selectivity of these lead therapeutic agents, but requires strategies for delivering the active agents to cells. One novel approach to achieving high cell permeability is to use small molecule precursors to the ultimate larger, bi- or oligo-valent ligand that are programmed to covalently self-assemble within the cell. Strategies for assembling active agents within cells that are being pursued include template-assisted synthesis and the nanoparticle-catalyzed construction of complex structures.

2:00 PM

Targeting Structurally and Functionally Diverse RNAs with Druglike Small Molecules


John Schneekloth, PhD
National Cancer Institute
2:30 PM

Networking Coffee Break

3:00 PM

Selective Small Molecule Inhibition of an RNA Structural Element


John A. Howe, PhD
Merck & Co.

Riboswitches are non-coding RNA structures located in bacterial messenger RNAs that bind endogenous ligands, such as a specific metabolite or ion, to regulate gene expression. As such, riboswitches serve as a novel, yet largely unexploited, class of emerging drug targets. Demonstrating this potential, however, has proven difficult and is restricted to structurally similar antimetabolites and semi-synthetic analogs of their cognate ligand, thus greatly restricting the chemical space and selectivity sought for such inhibitors. We recently reported the discovery and characterization of ribocil, a highly selective chemical modulator of bacterial riboflavin (RF) riboswitches, which was identified in a phenotypic screen and acts as a structurally distinct synthetic mimic of the natural ligand, flavin mononucleotide (FMN), to repress riboswitch-mediated ribB gene expression and inhibit bacterial cell growth. Our findings indicate non-coding RNA structural elements may be more broadly targeted by synthetic small molecules than previously expected.

3:30 PM

High-Throughput Platform Assay Technology for the Discovery of pre-microRNA-Selective Small Molecule Probes​


Amanda L. Garner, PhD
University of Michigan

MicroRNAs (miRNA) are an emerging class of small RNAs that play critical roles in human development and disease. These micromanagers function at the level of post-transcriptional gene regulation, and alteration of miRNA expression levels have been implicated in cancer, obesity, diabetes, viral infections and autoimmune, neurodegenerative and cardiovascular diseases among others. As such, the targeting of miRNAs is considered attractive as a novel therapeutic strategy. A major bottleneck toward this goal, however, has been the identification of small molecule probes that are specific for select RNAs and methods that will facilitate such discovery efforts. Using pre-microRNAs as proof-of-concept, we have developed an innovative approach for assaying RNA-small molecule interactions that takes advantage of the power of catalytic signal amplification combined with the selectivity and bioorthogonality of click chemistry. Through this platform assay technology, which we term catalytic Enzyme-Linked Click Chemistry Assay or cat-ELCCA, we have designed a method that can be implemented in high-throughput, is virtually free of false read-outs and is general for all nucleic acids. Using cat-ELCCA, we are working toward the discovery of new chemical space for RNA to illuminate the druggability of this under-explored nucleic acid and provide the basis for the development of next-generation, RNA-targeted small molecule therapeutics for the management of human health. Our progress toward this goal will be discussed.

4:00 PM

Panel Discussion

4:45 PM

Closing Remarks and F1000 Poster Prize Presentation

5:00 PM

Networking Reception

6:00 PM