Short talk 6
Structure-based Design of RNA targeting Peptides

Presenting Author: Marvin Albers

Vrije Univ. Amsterdam, Chemistry and Pharmaceutical Sciences, De Boelelaan 1108, 1081 HZ Amsterdam, NL, m.a.albers@vu.nl

Author(s)
Marvin Albers¹, Prof. Dr. Tom Grossmann²

¹ Vrije Univ. Amsterdam

² Georg-August- Universität Göttingen

RNA is increasingly recognized as an attractive therapeutic target due to its central role in disease-associated pathways. However, designing high-affinity ligands remains challenging because RNA lacks well-defined binding pockets and adopts dynamic conformations. RNA-binding proteins, which have co-evolved with RNA, provide ideal templates for structure-guided ligand design for these challenging targets.

In this work, we explore structure-based design approaches to design high-affinity RNA-targeting peptides. Inspired by RNA-protein complexes, such as the Tomato Aspermy Virus protein 2b (TAV2b), we apply rational design principles to develop peptides that selectively bind RNA structures. To enhance their properties, we employ chemical engineering strategies such as hydrocarbon stapling, which improves protease stability and promotes cellular uptake. These optimized peptides ultimately yielded bioactive inhibitors with improved selectivity.

Furthermore, TAV2b served as a template for designing dimeric stapled peptides that bind and stabilize dsRNA. By promoting the cellular uptake of siRNA, these RNA-targeting peptides tackle a major bottleneck for the therapeutic application of RNA-based technologies.

 

Together, these approaches demonstrate how structure-guided approaches combined with chemical engineering can yield potent RNA-targeting ligands. Expanding such strategies will help accelerate the exploitation of RNA in drug discovery and diagnostics.

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