Don’t we all dream of a #Degrader toolbox for off-the-shelf #PROTACs against “undruggable” targets?!? This recent publication from the labs of Andrew Tsourkas and Michael J Mitchell at Penn Bioengineering is paving the way: https://lnkd.in/eK59rKHp The paper introduces #bioPROTACs, protein-based heterobifunctional degraders, as an efficient alternative to small-molecule PROTACs for targeted protein degradation. Similar to classical degraders, bioPROTACS comprise three domains: ✅ a target-binding warhead, ✅ an E3-recruiting ligand, ✅ a chemical linker separating the two binding moieties. Here, #DARPins were used as warheads, building on unique #DARPin advantages like ☑ reliable and stable folding (in this case allowing for highly efficient #LNP encapsulation), ☑ specific and high affinity binding (for highly specific target engagement), ☑ entire functionality in the cytoplasm, which is crucial for the efficient delivery and action of degraders. Strikingly, the tested #bioPROTACs exhibited up to 95% clearance of targets within hours, representing a significant advancement in intracellular protein degradation and therapeutic potential. 𝘼𝙣𝙙 𝙬𝙝𝙖𝙩 𝙖𝙗𝙤𝙪𝙩 𝙩𝙝𝙚 “𝘿𝙚𝙡𝙞𝙫𝙚𝙧𝙮 𝙘𝙤𝙣𝙪𝙣𝙙𝙧𝙪𝙢”? 𝙃𝙤𝙬 𝙙𝙞𝙙 𝙩𝙝𝙚𝙨𝙚 𝙥𝙧𝙤𝙩𝙚𝙞𝙣 𝙙𝙧𝙪𝙜𝙨 𝙜𝙚𝙩 𝙄𝙉𝙏𝙊 𝙩𝙝𝙚 𝙘𝙚𝙡𝙡? ⬅ well, simply as LNP payload, like described earlier (https://lnkd.in/eGxfr45Y) ➡ For efficient LNP-encapsulation, the bioPROTAC format contains a C-terminal anionic polypeptide (ApP) domain that facilitates complexation with cationic and ionizable lipids. Thus, LNPs could be used as vectors to ensure efficient cytosolic delivery and function. Importantly, by simply switching the DARPin domains in a “plug and play”-like fashion, the bioPROTACs could be reprogrammed to polyubiquitinate diverse substrates including Ras, Erk, and Jnk for degradation. In the initial in vitro setting, the platform demonstrated robust, low nanomolar activity across different cell lines. This study highlights bioPROTACs' potential to overcome limitations of small-molecule inhibitors, offering a promising approach for new therapeutic strategies to address unmet medical needs in oncology and other therapeutic areas by targeting "undruggable" proteins. #biotechnology #drugdevelopment
Christian Jost
3mo
Vittoria Massafra, would be keen to get your take on this!
André São Pedro
3mo
That’s the first time that I see the term “delivery conundrum” used in this context and it made totally sense 😅 Always learning…
Athebio AG
3mo
Kudos to all additional co-authors: Alexander Chan, Rebecca Haley, Mohd Altaf Najar, David Gonzalez-Martinez, Lukasz Bugaj and George Burslem
Wai Lam Ling
3mo
Thanks for sharing Athebio AG. Very interesting inhibition data comparing protein and mRNA encapsulated LNP. An exciting path for #bioPROTAC
Gene therapy formulation specialist: AAV + mRNA/LNP. Nanoparticle Nerd.
3moThanks for highlighting Athebio AG & Christian! Upon initially reading this, I thought the bioProtac would be delivered encoded as mRNA in the LNP. Without having read about the protein design of the bioPROTAC too much, do you think these could be encoded in mRNA to become even less of a hassle to develop? (since the manufacturing would be identical no matter which bioPROTAC you'd choose to be encoded as mRNA?)