2. Academic Validation
  3. Discovery of the first potent and selective Mycobacterium tuberculosis Zmp1 inhibitor

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.
Mattia Mori 1,  Francesca Moraca 2,  Davide Deodato 2,  Davide M Ferraris 3,  Petra Selchow 4,  Peter Sander 5,  Menico Rizzi 3,  Maurizio Botta 6
Affiliations

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.

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