In Situ Click Chemistry: Enzyme-Generated Inhibitors of Carbonic Anhydrase II

Target‐guided synthesis: Rather than making and screening thousands of compounds for lead discovery, in situ click chemistry employs the biological target itself to assemble its inhibitors by selectively binding and interconnecting reagents within the confines of its binding sites. Subnanomolar inhi...

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Published inAngewandte Chemie International Edition Vol. 44; no. 1; pp. 116 - 120
Main Authors Mocharla, Vani P., Colasson, Benoit, Lee, Lac V., Röper, Stefanie, Sharpless, K. Barry, Wong, Chi-Huey, Kolb, Hartmuth C.
Format Journal Article
LanguageEnglish
Published Weinheim WILEY-VCH Verlag 17.12.2004
WILEY‐VCH Verlag
Wiley
Subjects
azides
Azides - chemistry
Benzenesulfonamides
Carbonic Anhydrase II - antagonists & inhibitors
Carbonic Anhydrase Inhibitors - chemical synthesis
Carbonic Anhydrase Inhibitors - chemistry
Carbonic Anhydrase Inhibitors - pharmacology
Chemistry
Chemistry, Multidisciplinary
Combinatorial Chemistry Techniques - methods
Crystallography, X-Ray
Cyclization
enzymes
high-throughput screening
inhibitors
Molecular Structure
Physical Sciences
Science & Technology
Structure-Activity Relationship
Sulfonamides - chemistry
template synthesis
inhibitors
template synthesis
ACTIVE-SITE
high-throughput screening
enzymes
TERMINAL ALKYNES
azides
DISCOVERY
LIBRARIES
VANCOMYCIN-RESISTANT BACTERIA
CONCANAVALIN-A
GLYCINAMIDE RIBONUCLEOTIDE TRANSFORMYLASE
ACETYLCHOLINESTERASE
AGENTS
ACCELERATED COMBINATORIAL SYNTHESIS
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Summary:Target‐guided synthesis: Rather than making and screening thousands of compounds for lead discovery, in situ click chemistry employs the biological target itself to assemble its inhibitors by selectively binding and interconnecting reagents within the confines of its binding sites. Subnanomolar inhibitors of carbonic anhydrase II were produced by the enzyme from simple azide and acetylene precursors (see picture).
Bibliography:istex:2B122BA329FB0C80C7462D84AD944D23A89EE688
ArticleID:ANIE200461580
ark:/67375/WNG-ST207P04-R
We thank the National Institute of General Medical Sciences, the National Institutes of Health (K.B.S., C.H.W.), the Skaggs Institute for Chemical Biology (H.C.K., K.B.S.; V.M. is a Skaggs Postdoctoral Fellow), and the W. M. Keck Foundation (K.B.S.) for financial support. We also thank Professor M. G. Finn and Professor V. V. Fokin for valuable discussions.
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ISSN:1433-7851
1521-3773
DOI:10.1002/anie.200461580