Peptide-derived bioavailable macrocycles as inhibitors of protein-RNA and protein-protein interactions

Project Information

PEP-PRO-RNA

Grant agreement ID: 678623

DOI

10.3030/678623

Project closed

EC signature date 25 February 2016

Start date 1 March 2016

End date 31 August 2021

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 499 268,75

EU contribution

€ 1 499 268,75

Coordinated by

STICHTING VU
Netherlands

Periodic Reporting for period 4 - PEP-PRO-RNA (Peptide-derived bioavailable macrocycles as inhibitors of protein-RNA and protein-protein interactions)

Reporting period: 2020-09-01 to 2021-08-31

Summary of the context and overall objectives of the project

Over the last decade, drug discovery faced the problem of decreasing success rates which is mainly caused by the fact that numerous novel biological targets are reluctant to classic small molecule modulation. In particular, that holds true for PPIs and PRIs. Approaches that allow the modulation of these interactions provide access to therapeutic agents targeting crucial biological processes that have been considered undruggable so far. The objective of this proposal is the elucidation of general principles for the design of bioavailable peptide-derived macrocyclic compounds and their use for the development of inhibitors of protein‒protein (PPI) and protein‒RNA interactions (PRI). It is proposed to use irregularly structured peptide binding epitopes as starting point for the design of bioactive macrocycles. In a two-step process, high target affinity and bioavailability are installed: a) Peptide macrocyclization for the stabilization of the irregular bioactive secondary structure, and b) Evolution of the cyclic peptide into a bioavailable macrocyclic compound. Using a well-characterized model system developed in my lab, initial design principles will be elucidated. These principles are subsequently used and refined for the development of macrocyclic inhibitors of protein‒protein interactions (PPI) and of protein‒RNA interactions (PRI). The protein‒protein and protein‒RNA complexes selected as targets are of therapeutic interest and corresponding inhibitors hold the potential to be pursued in subsequent drug discovery campaigns.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

- The potential of novel macroyclzation strategies was explored focusing on the use of ring-closing alkyne metathesis for the stabilization of an irregular peptide secondary structure. (publication: Cromm et al. ChemBioChem, 2016).
- Contribution of flexibilty of the bound ligand to target binding was investigated. (Colaboration partner: Christoph Rademacher, MPI Potsdam; publicaiton: Glas et al. Chem. Eur. J. 2017).
- We investigated the potential of computational approaches for the affintiy maturation of macrocyclic peptide ligands. (Colaboration parnter: Sven Hennig, VU Amsterdam; Oliver Koch, TU Dortmund; publication: Krüger et al. J. Med. Chem. 2017).
- We developed a stapled peptide inhibitor that targets the interaction between b-catenin and T cell factor/lymphoid enhancer-binding factor transcription factors, which are crucially involved in Wnt signaling. (collaboration partners: Trevor C. Dale, Cardiff University; Stefan Heinrichs, Uniklinikum Essen; Dennis Schade, University Greifswald; Tanja Bange, MPI Dortmund; publication: Dietrich et al. Cell Chem. Biol. 2017)
- We developt a strategy for the stabilization of protein tertiary structures (Pelay-Gimeno et al. Angewandte Chemie 2018).
- We analyzed the protein-RNA structures and developed a tool for the prediction of hotspots in the corresponding interfaces (publication: Krüger et al. RNA 2018).
- In collaboration with the groups of Janusz Bujnicki, Roland Brock and Stefan Heinrichs cell-permeable RNA-targeting proteomimetics were developed (publication: Kuepper et. al. Nucleic Acids Res. 2021)
- Selective inhibitors of the oncogenic Wnt signalling pathway were developed and characterised (publication: Wendt et al. Angewandte Chemie 2021)

--> The project has resulted in two ERC proof-of-concept grants and the formation of a spin-off company

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Summary of major achievments so far:
- A computational tool that facilitates affinity maturation of flexible macrocyclic peptide ligands has been developed.
- Cell-permeble and selective inhibitor of the protein beta-catenin has been designed.
- Insights into the requirements for selective RNA binding.
- Cell-permeable proteomimetic inhibitor of double-stranded RNA

Overview of project aims