Structure-based discovery of a family of synthetic cyclophilin inhibitors showing a cyclosporin-A phenotype in Caenorhabditis elegans

Yang, Y., Moir, E., Kontopidis, G., Taylor, P., Wear, M. A., Malone, K., Dunsmore, C. J., Page, A. P., Turner, N. J. and Walkinshaw, M. D. (2007) Structure-based discovery of a family of synthetic cyclophilin inhibitors showing a cyclosporin-A phenotype in Caenorhabditis elegans. Biochemical and Biophysical Research Communications, 363(4), pp. 1013-1019. (doi: 10.1016/j.bbrc.2007.09.079) (PMID:17927958)

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Publisher's URL: http://dx.doi.org/10.1016/j.bbrc.2007.09.079

Abstract

Cyclophilins, which are found in all cellular compartments and with diverse biological roles, are now drug targets for a number of diseases including HIV infection, malaria and ischaemia. We used the database-mining program LIDAEUS and in silico screening to discover the dimedone family of inhibitors which show a conserved 'ball and socket' binding mode with a dimethyl group in the hydrophobic binding pocket of human cyclophilin A (CypA) mimicking a key interaction of the natural inhibitor cyclosporin A (CsA). The most potent derivative binds CypA with a K(d) of 11.2+/-9.2 microM and an IC50 for activity against Caenorhabditis elegans (C. elegans) of 190 microM compared to 28 microM for CsA. These dimedone analogues provide a new scaffold for the synthesis of families of peptidomimetic molecules with potential activity against HIV, malaria, and helminth parasite infections.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Page, Professor Tony and Walkinshaw, Mr Malcolm
Authors: Yang, Y., Moir, E., Kontopidis, G., Taylor, P., Wear, M. A., Malone, K., Dunsmore, C. J., Page, A. P., Turner, N. J., and Walkinshaw, M. D.
Subjects:Q Science > QH Natural history > QH345 Biochemistry
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Biochemical and Biophysical Research Communications
Publisher:Elsevier
ISSN:0006-291X
ISSN (Online):1090-2104
Published Online:01 October 2007
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
229991The Molecular Enzymology of Collagen Assembly and Post-Translational Modification: a Nematode Model SystemAntony PageMedical Research Council (MRC)G117/290Infection Immunity and Inflammation Life Sciences
407991Chemical mapping of the PPIase interactome in C elegans - development of a systems biology toolboxAntony PageBiotechnology and Biological Sciences Research Council (BBSRC)BB/D006201/1Infection Immunity and Inflammation Life Sciences
229993The Molecular Enzymology of Collagen Assembly and Post-Translational Modification: a Nematode Model SystemAntony PageMedical Research Council (MRC)G117/476III - PARASITOLOGY