Probing the Bioactive Conformation of an Archetypal Natural Product HDAC Inhibitor with Conformationally Homogeneous Triazole-Modified Cyclic Tetrapeptides

Fooling enzymes with mock amides: Analogues of apicidin, a cyclic-tetrapeptide inhibitor of histone deacetylase (HDAC), were designed with a 1,4- or 1,5-disubstituted 1,2,3-triazole in place of a backbone amide bond to fix the bond in question in either a trans-like or a cis-like configuration. Thus...

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Published inAngewandte Chemie (International ed.) Vol. 48; no. 26; pp. 4718 - 4724
Main Authors Horne, W. Seth, Olsen, Christian A, Beierle, John M, Montero, Ana, Ghadiri, M. Reza
Format Journal Article
LanguageEnglish
Published Weinheim Wiley-VCH Verlag 01.01.2009
WILEY‐VCH Verlag
Wiley
Subjects
Chemistry
Chemistry, Multidisciplinary
cyclic peptides
drug design
enzyme inhibitors
Enzyme Inhibitors - chemistry
Histone Deacetylase Inhibitors
Histone Deacetylases - metabolism
Peptides, Cyclic - chemistry
Physical Sciences
Protein Conformation
Science & Technology
Stereoisomerism
Structure-Activity Relationship
structure–activity relationships
triazoles
Triazoles - chemistry
AZIDE-ALKYNE CYCLOADDITION
drug design
CLICK CHEMISTRY
triazoles
RUTHENIUM-CATALYZED CYCLOADDITION
SOLID-PHASE
CIS
cyclic peptides
CYCLOSPORINE-A
structure-activity relationships
AMINO-ACIDS
BIOLOGICAL EVALUATION
enzyme inhibitors
HISTONE DEACETYLASE INHIBITORS
BOND
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Summary:Fooling enzymes with mock amides: Analogues of apicidin, a cyclic-tetrapeptide inhibitor of histone deacetylase (HDAC), were designed with a 1,4- or 1,5-disubstituted 1,2,3-triazole in place of a backbone amide bond to fix the bond in question in either a trans-like or a cis-like configuration. Thus, the binding affinity of distinct peptide conformations (see picture) could be probed. One analogue proved in some cases to be superior to apicidin as an HDAC inhibitor.
Bibliography:http://dx.doi.org/10.1002/anie.200805900
These authors contributed equally to this work.
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We thank Dr. Dee Huang and Dr. Laura Pasternack for assistance with NMR spectroscopy, Dr. Sheo Singh for providing the coordinates of the published NMR structure of apicidin in [D
pyridine, Dr. Michael Kranz for providing the coordinates of the calculated lowest‐energy conformations of apicidin, Dr. Michael Pique for assistance in the preparation of the frontispiece graphics, and Dr. L. J. Leman for assistance in manuscript preparation. We acknowledge the National Science Foundation (W.S.H.) and NASA Earth and Space Science Fellowship Program (grant NNX07AR35H; J.M.B.) for predoctoral fellowships. A.M. thanks the Spanish Ministry for Science and Education for a Fulbright/MEC postdoctoral fellowship. C.A.O. thanks the Lundbeck Foundation and the Danish Research Council for Technology and Production Sciences (274‐06‐0317) for postdoctoral fellowships, and the Danish Independent Research Council for a Young Researcher's Award. This research was supported in part by a grant from the National Institute of General Medical Sciences (GM52190) and by the Skaggs Institute for Chemical Biology. HDAC=histone deacetylase.
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ISSN:1433-7851
1521-3773
DOI:10.1002/anie.200805900