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
  • 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: [email protected].
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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