Lecture

PROTACs: Catalytic Protein Knockdown Strategy

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In course

CH-317: Drug discovery and development

This course discusses the molecular basis of diseases and how drugs work. Concepts and processes employed in today's drug discovery and development are covered. The first part of the course focuses on small molecule drugs and the second one on biotherapeut ...

Description

This lecture introduces the concept of Proteolysis Targeting Chimeras (PROTACs), a method that recruits specific protein targets to an E3 ubiquitin ligase for ubiquitination and degradation. The lecture discusses the catalytic behavior of PROTACs, their ability to reduce protein levels significantly at low concentrations, and their potential in tumor xenografts. It also covers the design and testing of PROTACs, including their specificity, mechanism of action, and in vivo experiments. The lecture concludes with a discussion on the ternary complex involved in PROTACs and alternative techniques in drug development.

Instructor

Christian Heinis

Teaching & PhD PhD Students Thomas Julien Denis Emel, Alessandro Scapozza, Nathan Moïse De Sadeleer, Florian Handel, Hugo André Clerc, Frédéric Brantschen, Grégoire Menoud, Ines Michrafy, Jonathan Schmitt, Laura Elena Massaad Past EPFL PhD Students Jeremy Touati, Shiyu Chen, Sophie Venet-Bonnot, Lisa Pollaro, Inmaculada Rentero Rebollo, Philippe Diderich, Charlotte Urech-Varenne, Silvia Bellotto, Davide Bertoldo, Alessandro Zorzi, Camille Villequey, Jonas Alfred Karl Wilbs, Grigory Karateev, Vanessa Carle

Official source

Related concepts (29)

Ubiquitin

Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ubiquitously. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Four genes in the human genome code for ubiquitin: UBB, UBC, UBA52 and RPS27A. The addition of ubiquitin to a substrate protein is called ubiquitylation (or, alternatively, ubiquitination or ubiquitinylation).

Ubiquitin ligase

A ubiquitin ligase (also called an E3 ubiquitin ligase) is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin from the E2 to the protein substrate. In simple and more general terms, the ligase enables movement of ubiquitin from a ubiquitin carrier to another thing (the substrate) by some mechanism. The ubiquitin, once it reaches its destination, ends up being attached by an isopeptide bond to a lysine residue, which is part of the target protein.

In vivo

Studies that are in vivo (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and plants, as opposed to a tissue extract or dead organism. This is not to be confused with experiments done in vitro ("within the glass"), i.e., in a laboratory environment using test tubes, Petri dishes, etc.

Alternative medicine

Alternative medicine is any practice that aims to achieve the healing effects of medicine despite lacking biological plausibility, testability, repeatability or evidence of effectiveness. Unlike modern medicine, which employs the scientific method to test plausible therapies by way of responsible and ethical clinical trials, producing repeatable evidence of either effect or of no effect, alternative therapies reside outside of medical science and do not originate from using the scientific method, but instead rely on testimonials, anecdotes, religion, tradition, superstition, belief in supernatural "energies", pseudoscience, errors in reasoning, propaganda, fraud, or other unscientific sources.

In vitro

In vitro (meaning in glass, or in the glass) studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology and its subdisciplines are traditionally done in labware such as test tubes, flasks, Petri dishes, and microtiter plates.

Related lectures (17)

Frontiers in Chemical Biology

Explores the druggable proteome, PROTACS strategy, ubiquitin attachment, and drug development paradigms.

Protein Induced Degradation: Druggability Strategy

Explores protein-induced degradation to enhance target druggability and the use of PROTACS in drug development.

Protein Function Regulation: Degradation Mechanisms

Covers the mechanisms of protein degradation, including the roles of the proteasome and autophagy in regulating protein function.

Designing Targeted Protein Degraders

Explores the design and validation of targeted protein degraders, including PROTACs and molecular glue compounds, emphasizing the importance of proper analyses and validations in TPD research.

Post-translational Modifications of Proteins