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A Modular Approach to the Discovery and Affinity Maturation of Sequence-Selective RNA-Binding Compounds

  • Benjamin L. MillerEmail author
Chapter
Part of the Topics in Medicinal Chemistry book series (TMC, volume 27)

Abstract

This chapter describes a strategy developed at the University of Rochester that relies on a two-step process for the generation of high-affinity, sequence-selective RNA-binding compounds with target-relevant biological activity. First, a natural product-inspired dynamic combinatorial library (DCL) is employed to rapidly produce “hit” compounds able to bind the target RNA. Second, a process of analog synthesis is employed to enhance affinity, bioavailability, and sequence selectivity. This strategy has been used to successfully produce compounds able to bind target RNAs with high (nanomolar) affinity, and target-relevant activity in cellular assays and in vivo. In particular, approaches to RNA targets of critical importance in Myotonic Dystrophy (a triplet repeat RNA-mediated disease) and in the life cycle of HIV will be discussed.

Keywords

Bioisosteres Dynamic combinatorial chemistry Frameshifting HIV Myotonic dystrophy Natural products 

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Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Department of DermatologyUniversity of Rochester Medical CenterRochesterUSA

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