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

Projektinformationen

HeartRepairKIT

ID Finanzhilfevereinbarung: 101155448

DOI

10.3030/101155448

Projekt abgeschlossen

EK-Unterschriftsdatum 4 März 2024

Startdatum 1 April 2024

Enddatum 31 März 2026

Finanziert unter

• Marie Skłodowska-Curie Actions (MSCA)

Gesamtkosten

Keine Daten

EU-Beitrag

€ 191 760,00

Koordiniert durch

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)

Berichtszeitraum: 2024-04-01 bis 2026-03-31

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

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.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

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.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

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.