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Bioorg Med Chem Lett. 2014 Jun 1;24(11):2508-11. doi: 10.1016/j.bmcl.2014.04.004. Epub 2014 Apr 13.

Discovery of the first potent and selective Mycobacterium tuberculosis Zmp1 inhibitor.

Author information

1
Dipartimento di Biotecnologie, Chimica e Farmacia, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy; CLNS Istituto Italiano di Tecnologia@Sapienza, Viale Regina Elena 291, 00161 Roma, Italy.
2
Dipartimento di Biotecnologie, Chimica e Farmacia, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.
3
Dipartimento di Scienze del Farmaco, University of Piemonte Orientale 'A. Avogadro', Viale Largo Donegani 2, 28100 Novara, Italy.
4
Institute of Medical Microbiology, University of Zurich, Gloriastrasse 32, CH-8006 Zurich, Switzerland.
5
Institute of Medical Microbiology, University of Zurich, Gloriastrasse 32, CH-8006 Zurich, Switzerland; National Reference Laboratory for Mycobacteria (NRLM), Gloriastrasse 32, CH-8006 Zurich, Switzerland.
6
Dipartimento di Biotecnologie, Chimica e Farmacia, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy; Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, BioLife Science Bldg., Suite 333, 1900 N 12th Street, Philadelphia, PA 19122, USA. Electronic address: botta.maurizio@gmail.com.

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 94 nM and a high selectivity for Zmp1 with respect to human Neprilysin.

KEYWORDS:

Enzyme inhibitors; Metalloproteases; Tuberculosis; Virtual screening; Zmp1

PMID:
24767848
DOI:
10.1016/j.bmcl.2014.04.004
[Indexed for MEDLINE]

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