Products Cited in Publications Worldwide Crosslinked Helical Fork: Towards a Rationally Designed Encodable Scaffold for the Sequence-Specific Targeting of Double-Stranded RNA

Crosslinked Helical Fork: Towards a Rationally Designed Encodable Scaffold for the Sequence-Specific Targeting of Double-Stranded RNA

Jonathan G. Kwok

Abstract

A long-standing goal in the field of chemical biology is coupling molecular recognition with the prowess of synthetic chemistry to produce novel compounds serving as chemical probes and therapeutic agents. One class of biomolecules that has gained considerable research focus and advancement for targeting is ribonucleic acid, RNA. Transcriptomic data have shown that both coding and non-coding RNA have critical roles in regulating every aspect of the central dogma of molecular biology. Although the research field continues to thrive in the development of RNA-binding ligands, current modalities are limited to targeting single-stranded and structurally complex RNA. The double-stranded RNA remains one of the most challenging structures to target. Double-stranded RNA is found in many functional tertiary and quaternary structured RNA and offers opportunities to modulate its biological activities. Herein, I describe my efforts for the design, synthesis, and biochemical and biophysical evaluations of a novel proteomimetic scaffold, referred to as the Crosslinked Helical Fork for the structure-and sequence-specific recognition of double-stranded RNA. Chapter 1 introduces the current advancements in targeting primary, secondary, and tertiary structured RNA. The topics for discussion will focus on modalities recognizing RNA in a sequence- or structured-specific manner and how current complex structured RNA are liganded. Chapter 2 describes the design and binding assessments of two ahelical RNA-binding peptides that mimic the groove-binding proteins Rnt1p from Saccharomyces cerevisiae and Tat from the equine infectious anemia virus. Chapter 3 addresses the issues from the results of Chapter 2 by introducing an encodable proteomimetic scaffold that mimics a dimeric a-helical RNA-binding viral protein binding in the major groove of double-stranded RNA. The synthetic scaffold was inspired by the Tomato Aspermy Virus 2b (TAV2b) protein. The chapter concludes with the firstgeneration design principles of targeting double-stranded RNA in a structure- and sequence-specific manner and future directions to improve the encodable scaffold. Additional supporting data can be found after Chapter 3 in the Appendix.

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DEPC

A1278981609-47-897%

DEPC

12.0/5g

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Triisopropylsilane

A1878656485-79-698%

Triisopropylsilane

55.0/100g

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