PROTAC Degraders

The application of targeted protein degradation technologies to G protein‐coupled receptors

“…Bringing the POI and the E3 ligase into proximity allows the E3 ligase to position an E2 ubiquitin-conjugating enzyme to transfer ubiquitin molecules onto a lysine residue in the target protein, tagging it for proteasomal degradation. Detail on the historical evolution of PROTACs can be found in other recent reviews (Békés et al, 2022;Bond & Crews, 2021;Chamberlain & Hamann, 2019;Ciulli & Hsia, 2022;Coleman & Crews, 2018;K. Li & Crews, 2022;Maneiro et al, 2021).…”

Development of a GC-376 Based Peptidomimetic PROTAC as a Degrader of 3-Chymotrypsin-like Protease of SARS-CoV-2

“…As a general rule for a PROTAC molecule, combining covalent bond formation with its reversibility is expected to represent the best condition to efficiently degrade target proteins in a cellular context. 55 Indeed, the reversibility ensures dissociation and recycling of the PROTAC molecule, whereas the covalency confers higher selectivity. 56 Overall, these effects favor low doses usage of PROTAC molecules.…”

“…This experiment revealed the complete recovery of the enzyme activity (SI, Figure S9), thus showing the reversibility of the covalent C–S bond formed between SARS-CoV-2 3CL Pro and PROTAC 1 . As a general rule for a PROTAC molecule, combining covalent bond formation with its reversibility is expected to represent the best condition to efficiently degrade target proteins in a cellular context . Indeed, the reversibility ensures dissociation and recycling of the PROTAC molecule, whereas the covalency confers higher selectivity .…”