H2020Индивидуална стипендия2021–2023

DELETER · DCAF E3 Ligase Exploration To Expand degRadation

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2021-05-01 → 2023-04-30
Финансиране от ЕС: 212 934 €
Участници: 1
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Методи за разграждане на протеини изследват как чрез специални молекули опасни протеини, например при рак, се маркират за унищожение от клетъчния „боклук“. Това помага за създаването на по-точни терапии и по-доброто разбиране на функциите на протеините в организма.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

DCAF E3 Ligase Exploration To Expand degRadation

Targeted protein degradation (TPD) is emerging as a new way to treat diseases that works differently from traditional therapies and has several advantages. Instead of inhibiting a protein by binding to it and preventing it from functioning, TPD hijacks protein degradation pathways, such as the ubiquitin-proteasome system, that naturally exist in our cells to completely destroy dangerous proteins associated with diseases such as cancer. Complete removal of a protein from the cells disrupts all of it's potentional functions, potentially leading to a bigger impact than just inhibiting one function with a traditional drug. TPD also has the potential to expand druggable space, in that it can target "undruggable" proteins that are of high therapeutic interest but have proven resistant to targeting with conventional drugs. The TPD approach could also improve precision of therapies, targeting only diseased tissue and minimising side effects and damage to healthy tissue. There are two main types of molecules that are used in TPD: molecular glues and Proteolysis Targeting Chimeras (PROTACs). Both of these molecules work by sticking two proteins together, causing one protein, called the ligase, to tag the other protein (the target) with a molecule called ubiquitin. The ubiquitin tag is recognised by the cells garbage disposal system called the proteasome, which destroys the target protein. Beyond disease therapy, TPD can also be used as a tool to help us understand normal and disease functions of proteins by removing them from healthy or diseased cells and looking at the consequences. In order to advance TPD and enhance its prospects for creating treatments for diseases, we are exploring different components of the protein degradation pathway known as the ubiquitin-proteasome system to better understand how they work. We also hope to find small molecule drugs that can manipulate this pathway for therapeutic benefits.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

PROteolysis TArgeting Chimeras (PROTACs) are molecules with therapeutic potential that induce degradation of target proteins involved in disease. PROTACs are composed of a ligand that binds an E3 ubiquitin ligase, chemically linked to a ligand for the target protein. Formation of a ternary complex between ligase, PROTAC and target protein leads to ubiquitination of the target, which is then recognised by the proteasome and degraded. The vast majority of PROTAC degraders developed to date recruit either the VHL or Cereblon E3 ligases, and only ~1% of the >600 known E3 ligases have been harnessed by this type of molecule. However, a given E3 ligase may not always form ternary complexes productive to ubiquitination for every target, and considerations such as organelle, cell type and tissue specificity warrant exploration of E3 ligases beyond those for which ligands currently exist. In this Fellowship, I will pursue the DCAF family of E3 ligases to expand the PROTAC toolbox. Two DCAF proteins have been successfully hijacked by degraders such as PROTACs, validating the family as exploitable for targeted protein degradation, and most DCAF proteins contain a WD40 repeat domain that is ligandable i.e. tractable to small molecule binding. Certain DCAF proteins also display organelle and tissue specificity. Beyond their potential for PROTAC development, DCAF proteins are therapeutically relevant in their own right and have been implicated in diseases such as cancer. DELETER will explore this high-potential yet understudied family of E3 ligases structurally, functionally and biophysically. High-quality recombinant proteins and relevant reagents produced in this project will be used to engage in screening campaigns to identify ligands that will be developed into PROTACs and inhibitors. The information, reagents and compounds generated for DCAFs will expand the scope of targeted protein degradation and has potential to increase the number of targets degradable by PROTACs.

Оригинален текст от CORDIS (на английски).

Участници

UNIVERSITY OF DUNDEE · DundeeКоординаторОбединеното кралство