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A new protein antagonist design strategy shows promise against leukaemia by targeting important receptors to stop the proliferation of cancer cells.
A new family of protein-based antagonists has been created by researchers that efficiently block the granulocyte-colony stimulating factor receptor (G-CSFR), which is essential for the development of leukaemia and other inflammatory illnesses. This groundbreaking work paves the way for targeted therapies that could revolutionise treatment options for patients suffering from these conditions.
Short Overview
• Disease Connection: Cancers, autoimmune illnesses, and inflammatory diseases are all associated with dysregulation of type 1 cytokine receptor signalling, which makes them important targets for treatment.
• Strategy: Developing antagonists or inhibitors for these receptors is a promising method to treating cancer, autoimmune and inflammatory diseases.
• Protein Design Innovation: To produce stable, non-activating protein variations that efficiently block receptor signalling, the research team employed cutting-edge protein design approaches. The elements of the design strategy:
o Simplified protein structure: By altering the fold of signaling proteins, the researchers built simpler and smaller binders, that are easier to produce and handle, which they demonstrate against three different receptors (G-CSFR, GP-130, and TPOR).
o Enhanced Stability: The proteins that have been engineered to exhibit both structural and functional stability, guaranteeing their prolonged functionality.
o Improved Binding Affinity: The newly designed G-CSFR antagonists could outcompete the original ligand by binding with higher affinity.
o Grafting two binding sites onto a single molecule: The designed antagonists dimerize the receptor subunits in an unfavorable (non-signalling) orientation, that spaces apart the intracellular parts of the receptor.
• Therapeutic Potential: By improving patient outcomes and reducing adverse effects, this research may result in novel therapeutic options for autoinflammatory disorders and leukaemia.
Overall, the findings from this study could significantly advance the development of new therapeutic options for leukaemia and autoinflammatory diseases, minimising side effects and improving patient outcomes and quality of life.
Engineering Protein-Based Antagonists
In a significant advancement for cancer research, a team of scientists from Max Planck Institute for Biology Tübingen, University Hospital Tübingen, and Osnabrück University successfully designed protein-based antagonists that selectively block the G-CSFR receptor, which is linked to the emergence of several blood cancers, including acute myeloid leukaemia. This innovative method gives patients and their families new hope by increasing the efficacy of cancer therapies and reducing possible side effects.
A healthy immune response depends on the creation and function of white blood cells, regulated mainly by the G-CSFR. On the other hand, overactivity of this receptor may result in unchecked cell proliferation and the emergence of cancer. The lack of specificity in many current medications results in systemic adverse effects that can seriously lower a patient's quality of life. To overcome this difficulty, the recently developed antagonists offer a focused method of blocking G-CSFR signalling.
“What was particularly interesting is the sensitivity of the receptor activity to its association geometry, where controlling the geometry can tap into a spectrum of signalling outcomes,” stated Dr Mohammad ElGamacy, the lead researcher and Research Group Leader at the University Hospital Tübingen.
To create stable, highly affine G-CSFR antagonists that would outcompete the native ligand, the research team employed de novo-designed protein template to create bivalent binders. The resulting bifaceted designs bind the receptor more tightly and prevent its dimerization into a signalling configuration in cell membranes. This technique allows antagonists to block the receptor efficiently and have improved thermal and proteolytic stability, which qualifies them for therapeutic application. The outcomes showed the promise of these antagonists as a novel class of targeted therapeutics by showing that they could dramatically lower the growth of leukaemia cells in lab settings.
Next Steps in Research and Development
The implications of this discovery extend beyond leukaemia treatment. The engineered antagonists could also be applied to other conditions characterised by G-CSFR dysregulation, including various autoimmune and inflammatory diseases. The research team's focus is to conduct further preclinical studies to evaluate the safety and efficacy of these antagonists in vivo and advance to clinical trials in the near future.
In conclusion, this groundbreaking work represents a significant step forward in searching for more effective and targeted cancer therapies. By harnessing the power of protein design, researchers are paving the way for innovative treatments that could improve outcomes for patients battling leukaemia and other related diseases. The potential to personalise medicine based on individual patient profiles further underscores the importance of this research, as it aims to provide tailored solutions that address the unique challenges posed by these complex conditions.
Lead Researcher
Dr. Mohammad ElGamacy
Translationale Onkologie
Innere Medizin II, Universitätsklinikum Tübingen
mohammad.elgamacy@med.uni-tuebingen.de
Press Office
Beatriz Lucas
Max Plank Institute for Biology Tübingen
presse-bio@tuebingen.mpg.de
Ullrich T, Klimenkova O, Pollmann C, Lasram A, Hatskovska V, Maksymenko K, Milijaš-Jotić M, Schenk L, Lengerke C, Hartmann M D, Piehler J, Skokowa J, ElGamacy M (2024) A strategy to design protein-based antagonists against type I cytokine receptors. PLoS Biol 22(11): e3002883. https://doi.org/10.1371/journal.pbio.3002883
http://Press release: https://www.bio.mpg.de/420187/news_publication_23944571_transferred?c=57217
http://Download PDF and image: https://keeper.mpdl.mpg.de/d/7d2a9f33c8c848c68746/
Revolutionising Cancer Therapy with Protein Design
© Dr. Kateryna Maksymenko/ Max Planck Institute for Biology Tübingen, Germany.
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Revolutionising Cancer Therapy with Protein Design
© Dr. Kateryna Maksymenko/ Max Planck Institute for Biology Tübingen, Germany.
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