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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-5039

Schenker, P; Alfarano, P; Kolb, P; Caflisch, A; Baici, A (2008). A double-headed cathepsin B inhibitor devoid of warhead. Protein Science : a Publication of the Protein Society, 17(12):2145-2155.

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Abstract

Most synthetic inhibitors of peptidases have been targeted to the active site for inhibiting catalysis through reversible competition with the substrate or by covalent modification of catalytic groups. Cathepsin B is unique among the cysteine peptidase for the presence of a flexible segment, known as the occluding loop, which can block the primed subsites of the substrate binding cleft. With the occluding loop in the open conformation cathepsin B acts as an endopeptidase and as an exopeptidase when the loop is closed. We have targeted the occluding loop of human cathepsin B at its surface, outside the catalytic center, using a high-throughput docking procedure. The aim was to identify inhibitors that would interact with the occluding loop thereby modulating enzyme activity without the help of chemical warheads against catalytic residues. From a large library of compounds, the in silico approach identified [2-[2-(2,4-dioxo-1,3-thiazolidin-3-yl)ethylamino]-2-oxoethyl] 2-(furan-2-carbonylamino)acetate, which fulfils the working hypothesis. This molecule possesses two distinct binding moieties and behaves as a reversible, double-headed competitive inhibitor of cathepsin B by excluding synthetic and protein substrates from the active center. The kinetic mechanism of inhibition suggests that the occluding loop is stabilized in its closed conformation, mainly by hydrogen bonds with the inhibitor, thus decreasing endoproteolytic activity of the enzyme. Furthermore, the dioxothiazolidine head of the compound sterically hinders binding of the C-terminal residue of substrates resulting in inhibition of the exopeptidase activity of cathepsin B in a physiopathologically relevant pH range.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Department of Biochemistry
07 Faculty of Science > Department of Biochemistry
DDC:570 Life sciences; biology
Language:English
Date:2008
Deposited On:08 Jan 2009 10:57
Last Modified:27 Nov 2013 18:38
Publisher:Wiley-Blackwell
ISSN:0961-8368
Additional Information:The attached file is a preprint (accepted version) of an article published in Protein Science : a Publication of the Protein Society 2008, 17(12):2145-2155
Publisher DOI:10.1110/ps.037341.108
Official URL:http://www3.interscience.wiley.com/journal/121603578/abstract
PubMed ID:18796695

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