Sequestration of MBNL1 by (CUG) repeat RNA is believed to be a key molecular interaction in type 1 myotonic dystrophy (DM1). Thus, new compounds able to inhibit this interaction constitute important potential leads towards the development of effective therapeutic agents. We recently described the discovery of a set of compounds able to bind (CUG) repeat RNA with significant selectivity and inhibit MBNL1 binding. Our proposed research centers on three Aims that will expand on this important initial result, and obtain compounds suitable for clinical development. First, we will determine the minimum binding peptide capable of maintaining selective (CUG) repeat RNA binding, and will explore the effect of peptide N-methylation on affinity. Second, we will employ the highest-affinity lead compound in a displacement-based high throughput screen for new (CUG) repeat-binding chemotypes. Finally, we will carry out a series of cellular assays to determine the ability of new compounds to inhibit (CUG) RNA - MBNL1 binding in a cellular context.

Public Health Relevance

Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy in adults, affecting 1 in 8000 people. The disease is believed to result from the accumulation of a toxic RNA, termed a """"""""CUG repeat"""""""", which sequesters a protein critical for proper cellular function. Building on a discovery made in our laboratory of a molecule able to bind CUG repeat RNA, we will carry out a series of experiments designed to yield a new molecule with higher activity and improved drug-like properties. The overall goal of the project will be to obtain at least one compound suitable for development as a therapeutic agent.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS071023-01
Application #
7963320
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Porter, John D
Project Start
2010-07-15
Project End
2012-06-30
Budget Start
2010-07-15
Budget End
2011-06-30
Support Year
1
Fiscal Year
2010
Total Cost
$208,300
Indirect Cost
Name
University of Rochester
Department
Dermatology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Yadav, Amrita R; Mace, Charles R; Miller, Benjamin L (2014) Examining the interactions of the splicing factor MBNL1 with target RNA sequences via a label-free, multiplex method. Anal Chem 86:1067-75
Hoskins, Jason W; Ofori, Leslie O; Chen, Catherine Z et al. (2014) Lomofungin and dilomofungin: inhibitors of MBNL1-CUG RNA binding with distinct cellular effects. Nucleic Acids Res 42:6591-602
Ofori, Leslie O; Hoskins, Jason; Nakamori, Masayuki et al. (2012) From dynamic combinatorial 'hit' to lead: in vitro and in vivo activity of compounds targeting the pathogenic RNAs that cause myotonic dystrophy. Nucleic Acids Res 40:6380-90
Gromova, Anna V; Ciszewski, Joseph M; Miller, Benjamin L (2012) Ternary resin-bound Dynamic Combinatorial Chemistry. Chem Commun (Camb) 48:2131-3