Designed ankyrin repeat proteins (DARPins) as novel isoform-specific intracellular inhibitors of c-Jun N-terminal kinases

ACS Chemical Biology
Petra ParizekAndreas Plückthun

Abstract

The c-Jun N-terminal kinases (JNKs) are involved in many biological processes such as proliferation, differentiation, apoptosis, and inflammation and occur in highly similar isoforms in eukaryotic cells. Isoform-specific functions and diseases have been reported for individual JNK isoforms mainly from gene-knockout studies in mice. There is, however, a high demand for intracellular inhibitors with high selectivity to improve the understanding of isoform-specific mechanisms and for use as therapeutic tools. The commonly used JNK inhibitors are based on small molecules or peptides that often target the conserved ATP binding site or docking sites and thus show only moderate selectivity. To target novel binding epitopes, we used designed ankyrin repeat proteins (DARPins) to generate alternative intracellular JNK inhibitors that discriminate two very similar isoforms, JNK1 and JNK2. DARPins are small binding proteins that are well expressed, stable, and cysteine-free, which makes them ideal candidates for applications in the reducing intracellular environment. We performed ribosome display selections against JNK1α1 and JNK2α1 using highly diverse combinatorial libraries of DARPins. The selected binders specifically recognize either ...Continue Reading

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Citations

Jul 31, 2012·Proceedings of the National Academy of Sciences of the United States of America·Lutz KummerAndreas Plückthun
Mar 29, 2014·Protein Engineering, Design & Selection : PEDS·Christian TiedeMichael J McPherson
Jan 27, 2016·Journal of Molecular Biology·Marco SchützAndreas Plückthun
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Apr 9, 2016·ACS Chemical Biology·Amy E Rabideau, Bradley Lether Pentelute
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Jun 12, 2012·New Biotechnology·Oda Stoevesandt, Michael J Taussig
Jun 26, 2013·Chemistry & Biology·Lutz KummerAndreas Plückthun
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Jul 15, 2017·Nature Communications·Sandrine GuillardRalph Minter
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Jan 10, 2020·Current Opinion in Structural Biology·Peer Re MittlAndreas Plückthun
Jul 18, 2020·Current Opinion in Pharmacology·Achille Patrizio Caputi, Pierluigi Navarra

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