Issue 31, 2023

Rationally designed stapled peptides allosterically inhibit PTBP1–RNA-binding


The diverse role of the splicing factor PTBP1 in human cells has been widely studied and was found to be a driver for several diseases. PTBP1 binds RNA through its RNA-recognition motifs which lack obvious pockets for inhibition. A unique transient helix has been described to be part of its first RNA-recognition motif and to be important for RNA binding. In this study, we further confirmed the role of this helix and envisioned its dynamic nature as a unique opportunity to develop stapled peptide inhibitors of PTBP1. The peptides were found to be able to inhibit RNA binding via fluorescence polarization assays and directly occupy the helix binding site as observed by protein crystallography. These cell-permeable inhibitors were validated in cellulo to alter the regulation of alternative splicing events regulated by PTBP1. Our study demonstrates transient secondary structures of a protein can be mimicked by stapled peptides to inhibit allosteric mechanisms.

Graphical abstract: Rationally designed stapled peptides allosterically inhibit PTBP1–RNA-binding

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Article information

Article type
Edge Article
21 Feb 2023
28 Jun 2023
First published
13 Jul 2023
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2023,14, 8269-8278

Rationally designed stapled peptides allosterically inhibit PTBP1–RNA-binding

S. Schmeing, G. Amrahova, K. Bigler, J. Chang, J. Openy, S. Pal, L. Posada, R. Gasper and P. 't Hart, Chem. Sci., 2023, 14, 8269 DOI: 10.1039/D3SC00985H

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