Click Chemistry In Situ: Acetylcholinesterase as a Reaction Vessel for the Selective Assembly of a Femtomolar Inhibitor from an Array of Building Blocks
Warren G. Lewis
Department of Chemistry The Scripps Research Institute 10550 North Torrey Pines Road La Jolla, CA 92037 (USA) Fax: (+1) 858-784-7562
Search for more papers by this authorLuke G. Green Dr.
Department of Chemistry The Scripps Research Institute 10550 North Torrey Pines Road La Jolla, CA 92037 (USA) Fax: (+1) 858-784-7562
Search for more papers by this authorFlavio Grynszpan Prof.
Department of Molecular Biology The Scripps Research Institute 10550 North Torrey Pines Road La Jolla, CA 92037 (USA)
Search for more papers by this authorZoran Radić Dr.
Department of Pharmacology University of California San Diego La Jolla, CA 92093-0636 (USA)
Search for more papers by this authorPaul R. Carlier Prof.
Department of Chemistry Virginia Polytechnic Institute and State University Blacksburg, VA 24061 (USA)
Search for more papers by this authorPalmer Taylor Prof.
Department of Pharmacology University of California San Diego La Jolla, CA 92093-0636 (USA)
Search for more papers by this authorM. G. Finn Prof.
Department of Chemistry The Scripps Research Institute 10550 North Torrey Pines Road La Jolla, CA 92037 (USA) Fax: (+1) 858-784-7562
Search for more papers by this authorK. Barry Sharpless Prof.
Department of Chemistry The Scripps Research Institute 10550 North Torrey Pines Road La Jolla, CA 92037 (USA) Fax: (+1) 858-784-7562
Search for more papers by this authorWarren G. Lewis
Department of Chemistry The Scripps Research Institute 10550 North Torrey Pines Road La Jolla, CA 92037 (USA) Fax: (+1) 858-784-7562
Search for more papers by this authorLuke G. Green Dr.
Department of Chemistry The Scripps Research Institute 10550 North Torrey Pines Road La Jolla, CA 92037 (USA) Fax: (+1) 858-784-7562
Search for more papers by this authorFlavio Grynszpan Prof.
Department of Molecular Biology The Scripps Research Institute 10550 North Torrey Pines Road La Jolla, CA 92037 (USA)
Search for more papers by this authorZoran Radić Dr.
Department of Pharmacology University of California San Diego La Jolla, CA 92093-0636 (USA)
Search for more papers by this authorPaul R. Carlier Prof.
Department of Chemistry Virginia Polytechnic Institute and State University Blacksburg, VA 24061 (USA)
Search for more papers by this authorPalmer Taylor Prof.
Department of Pharmacology University of California San Diego La Jolla, CA 92093-0636 (USA)
Search for more papers by this authorM. G. Finn Prof.
Department of Chemistry The Scripps Research Institute 10550 North Torrey Pines Road La Jolla, CA 92037 (USA) Fax: (+1) 858-784-7562
Search for more papers by this authorK. Barry Sharpless Prof.
Department of Chemistry The Scripps Research Institute 10550 North Torrey Pines Road La Jolla, CA 92037 (USA) Fax: (+1) 858-784-7562
Search for more papers by this authorWe thank the National Institute of General Medical Sciences, National Institutes of Health (GM-28384, K.B.S.; R-37 GM 18360, P.T.), the National Science Foundation (CHE-9985553, K.B.S.), The Skaggs Institute for Chemical Biology (K.B.S., M.G.F.; W.G.L. is a Skaggs Predoctoral Fellow), the W. M. Keck Foundation (K.B.S.), and the J. S. Guggenheim Memorial Foundation (F.G.) for financial support. We are grateful to Dr. Pascale Marchot (University of Marseille, France) for providing us with a purified preparation of Electrophorus electricus AChE for kinetic measurements. We also thank Prof. D. W. Armstrong, C. Mitchell, Dr. G. M. Morris, Dr. X. Wu, Dr. Z. Shen, and Prof. G. Siuzdak for assistance in the execution of this project, and Professors V. V. Fokin and R. Ghadiri for valuable discussions. W.G.L. and L.G.G. contributed equally to this work.
Graphical Abstract
Maßgeschneiderte Chemie in einer Protein-Vorlage: Bei einer Reihe von Aziden und Alkinen, Reaktanten für eine 1,3-dipolare Cycloaddition, wird vom Enzym Acetylcholinesterase bevorzugt ein Paar von Reaktionspartnern umgesetzt, von denen beide an benachbarten Stellen in der Proteinstruktur binden (siehe Bild). Das dabei gebildete 1,2,3-Triazol ist der stärkste bisher entwickelte nichtkovalent gebundene Inhibitor für dieses Enzym.
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