From 4038451f4e16a5536b9db36b967f1af854b32b52 Mon Sep 17 00:00:00 2001 From: noemiesarah Date: Tue, 8 Oct 2024 19:11:12 +0200 Subject: [PATCH] Update index.md --- docs/index.md | 9 ++++----- 1 file changed, 4 insertions(+), 5 deletions(-) diff --git a/docs/index.md b/docs/index.md index 9193d4e..3c45ab5 100644 --- a/docs/index.md +++ b/docs/index.md @@ -10,23 +10,22 @@ hide: Diseases caused by the accumulation of excess or misfolded proteins or their unintended overactivity, such as Alzheimer's, Parkinson's, Huntington's disease, and certain cancers, pose a significant challenge in medicine. These conditions are often characterised by toxic protein aggregates or chronically active proteins that disrupt normal cellular functions, lead to cell death, and trigger chronic inflammation. Targeted Protein Degradation (TPD) has emerged as an exciting new therapeutic approach to combat these diseases by targeting and eliminating the problematic proteins that drive their progression[^ubi_first]. Unlike current TPD strategies, which can inadvertently affect healthy proteins, cause toxicity, or miss their intended targets, we aim to develop a more precise method of TPD that specifically targets disease-associated proteins while minimising off-target effects and toxicity. -The body naturally disposes of damaged proteins through a system known as the Ubiquitin-Proteasome System (UPS)[^ubi_fourth]. In this system, damaged or excess proteins are tagged with ubiquitin, a small protein that signals the cell’s machinery to degrade the tagged proteins. The proteasome, a cellular complex, then breaks down these proteins into harmless components. By leveraging this natural process, TPD offers a powerful strategy to selectively eliminate disease-associated proteins, offering the potential for more effective treatments with fewer side effects on healthy tissues. +The body naturally disposes of damaged proteins through a system known as the Ubiquitin-Proteasome System (UPS)[^ubi_fourth]. In this system, damaged or excess proteins are tagged with ubiquitin, a small protein that signals the cell’s machinery to degrade the tagged proteins. The proteasome, a cellular complex, breaks down these proteins into harmless components. By leveraging this natural process, TPD offers a powerful strategy to selectively eliminate disease-associated proteins, offering the potential for more effective treatments with fewer side effects on healthy tissues. ## Our Approach We are developing a novel approach that exploits the ability of the UPS to more effectively target proteins for degradation. Our strategy focuses on reprogramming a key player of this system, the E3 ubiquitin ligase[^ubi_second], to selectively recognise and degrade harmful proteins associated with disease. Using Phage-Assisted Continuous Evolution (PACE)[^pace_review], a powerful technique that mimics natural selection in the laboratory, we aim to engineer E3 ligases capable of targeting specific disease-causing proteins. By engineering these ligases to recognise specific substrates, we are working towards a platform that can rapidly produce customised ligases with precise recognition and degradation capabilities, providing a new avenue to treat diseases. - ## Our Workflow 1. Identification of reprogrammable E3 ligases and clinically relevant protein targets. -2. Construct selection system and test different promoters, linkers, substrates, among other things. -3. Achieve E3 ligase activity dependent phage propagation in the selection system. +2. Construct a selection system and test different promoters, linkers, and substrates, among other things. +3. Achieve E3 ligase activity-dependent phage propagation in the selection system. 4. Evolution of the E3 ligase towards recognising clinically relevant protein targets using Phage-Assisted Continous Evolution (PACE). 5. Confirmation of evolved E3 activity in bacterial system and mammalian cell lines. 6. Further work towards clinical use of the evolved E3 ligase for Targeted Protein Degradation. ## Key achievements: - +- test ## References [^ubi_first]:Tsai JM, Nowak RP, Ebert BL, Fischer ES. Targeted protein degradation: from mechanisms to clinic. Nat Rev Mol Cell Biol. 2024;25: 740–757. doi:10.1038/s41580-024-00729-9