Structural, kinetic, and biophysical analysis and engineering of KIT.METRNL signalling to boost heart tissue regeneration after myocardial infarction

Project Information

HeartRepairKIT

Grant agreement ID: 101155448

DOI

10.3030/101155448

Project closed

EC signature date 4 March 2024

Start date 1 April 2024

End date 31 March 2026

Funded under

• Marie Skłodowska-Curie Actions (MSCA)

Total cost

No data

EU contribution

€ 191 760,00

Coordinated by

VIB VZW
Belgium

Periodic Reporting for period 1 - HeartRepairKIT (Structural, kinetic, and biophysical analysis and engineering of KIT.METRNL signalling to boost heart tissue regeneration after myocardial infarction)

Reporting period: 2024-04-01 to 2026-03-31

Summary of the context and overall objectives of the project

Cardiovascular diseases are the leading cause of death worldwide, with millions of patients suffering from long-term complications after heart attacks. One of the major medical challenges is the limited ability of the heart to regenerate damaged tissue, which often results in reduced quality of life and high healthcare costs.

Recent scientific discoveries suggested that a protein called meteorin-like (METRNL) might stimulate heart tissue repair by interacting with a receptor called KIT, opening a potential new avenue for therapeutic development. However, the molecular details of this interaction were unknown, limiting its use in medicine.

The goal of the HeartRepairKIT project was to understand how KIT signalling towards cardiac regeneration works at the molecular level and to use this knowledge to develop improved protein-based agents that could enhance heart tissue repair. The project combined experimental and computational approaches, including structural biology, biophysics, and artificial intelligence (AI)-based protein design, with the broader aim of contributing to new strategies for cardiovascular therapy.

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

During the project, key experimental tools and methods were successfully developed, including the production of the required proteins and advanced techniques to study how they interact. An important finding was that the previously reported interaction between KIT and METRNL could not be confirmed using purified proteins in laboratory conditions. This result suggests that the interaction may depend on additional biological factors and highlights the importance of rigorous experimental validation.

To overcome this limitation, the research direction was adapted towards the design of artificial de novo protein binders capable of interacting with KIT, mimicking the biological role of the natural protein METRNL. Using state-of-the-art AI-based methods, a series of novel “minibinders” was developed and experimentally tested.

The project successfully:
• established new methods for studying protein interactions and signalling
• determined structural models of KIT in complex with designed binders
• identified extremely strong binders with affinities far exceeding those of natural molecules
• revealed detailed mechanisms of how KIT is activated at the molecular level

These results demonstrate the feasibility of designing new protein-based agents that can precisely control biological signalling pathways.

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)

The project advances the state of the art in several ways. First, it provides a deeper understanding of how receptor signalling works at the molecular level, including identification of key steps that control binding, avidity, and activation. Second, it demonstrates the power of combining experimental techniques with modern AI-based protein design to generate entirely new functional molecules.

The developed KIT-binding minibinders show exceptionally strong binding properties, significantly surpassing natural ligands. This opens new possibilities for designing targeted protein therapeutics. In the long term, these results could contribute to the development of new treatments aimed at improving recovery after heart attacks by enhancing tissue regeneration. Such advances could have significant societal and economic benefits by reducing long-term disability and healthcare costs.

Beyond direct medical applications, the computational and experimental methodologies developed in this project can be broadly applied in other areas of biotechnology and drug discovery, supporting innovation across the life sciences sector.

Further steps towards real-world application will include biological validation in cell-based and pre-clinical models, potential intellectual property protection, and collaboration with industry partners.