Discovery of the first potent and selective Mycobacterium tuberculosis Zmp1 inhibitor

Mattia Mori; Francesca Moraca; Davide Deodato; Davide M Ferraris; Petra Selchow; Peter Sander; Menico Rizzi; Maurizio Botta

doi:10.1016/j.bmcl.2014.04.004

Discovery of the first potent and selective Mycobacterium tuberculosis Zmp1 inhibitor

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

Authors

Mattia Mori¹, Francesca Moraca², Davide Deodato², Davide M Ferraris³, Petra Selchow⁴, Peter Sander⁵, Menico Rizzi³, Maurizio Botta⁶

Affiliations

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.

PMID: 24767848
DOI: 10.1016/j.bmcl.2014.04.004

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Bacterial Proteins / antagonists & inhibitors*
Bacterial Proteins / metabolism
Dose-Response Relationship, Drug
Drug Discovery*
Humans
Metalloproteases / antagonists & inhibitors*
Metalloproteases / metabolism
Models, Molecular
Molecular Structure
Neprilysin / antagonists & inhibitors
Neprilysin / metabolism
Protease Inhibitors / chemical synthesis
Protease Inhibitors / chemistry
Protease Inhibitors / pharmacology*
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology*
Structure-Activity Relationship

Substances

Bacterial Proteins
Protease Inhibitors
Small Molecule Libraries
Metalloproteases
Zmp1 protein, Mycobacterium tuberculosis
Neprilysin