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Discovery of the first potent and selective Mycobacterium tuberculosis Zmp1 inhibitor


Mori, Mattia; Moraca, Francesca; Deodato, Davide; Ferraris, Davide M; Selchow, Petra; Sander, Peter; Rizzi, Menico; Botta, Maurizio (2014). Discovery of the first potent and selective Mycobacterium tuberculosis Zmp1 inhibitor. Bioorganic & Medicinal Chemistry Letters, 24(11):2508-2511.

Abstract

The Mycobacterium tuberculosis extracellular zinc metalloprotease 1 (Zmp1) has been proposed to play a key role in phagosome maturation and to enhance the survival of Mycobacterium tuberculosis in the host. Consequently, small molecule inhibitors of Zmp1 are of pivotal importance as a tool to better understand the pathogenicity of Zmp1 and as lead candidates for pharmacological intervention. Here we combined in silico structure-based inhibitor design with biochemical studies to discover and characterize the first potent competitive Zmp1 inhibitor showing a Ki of 94nM and a high selectivity for Zmp1 with respect to human Neprilysin.

Abstract

The Mycobacterium tuberculosis extracellular zinc metalloprotease 1 (Zmp1) has been proposed to play a key role in phagosome maturation and to enhance the survival of Mycobacterium tuberculosis in the host. Consequently, small molecule inhibitors of Zmp1 are of pivotal importance as a tool to better understand the pathogenicity of Zmp1 and as lead candidates for pharmacological intervention. Here we combined in silico structure-based inhibitor design with biochemical studies to discover and characterize the first potent competitive Zmp1 inhibitor showing a Ki of 94nM and a high selectivity for Zmp1 with respect to human Neprilysin.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Medical Microbiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2014
Deposited On:04 Jun 2014 08:32
Last Modified:05 Apr 2016 17:54
Publisher:Elsevier
ISSN:0960-894X
Publisher DOI:https://doi.org/10.1016/j.bmcl.2014.04.004
PubMed ID:24767848

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