Discovery of the first potent and selective Mycobacterium tuberculosis Zmp1 inhibitor.
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.
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.
Mattia
M
Mori
Dipartimento di Biotecnologie, Chimica e Farmacia, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.
Francesca
F
Moraca
Dipartimento di Biotecnologie, Chimica e Farmacia, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.
Davide
D
Deodato
Dipartimento di Scienze del Farmaco, University of Piemonte Orientale 'A. Avogadro', Viale Largo Donegani 2, 28100 Novara, Italy.
Davide M
DM
Ferraris
Institute of Medical Microbiology, University of Zurich, Gloriastrasse 32, CH-8006 Zurich, Switzerland.
Petra
P
Selchow
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.
Peter
P
Sander
Dipartimento di Scienze del Farmaco, University of Piemonte Orientale 'A. Avogadro', Viale Largo Donegani 2, 28100 Novara, Italy.
Menico
M
Rizzi
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.
Maurizio
M
Botta
D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D045726:Metalloproteases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D015260:Neprilysin / Q000037:antagonists & inhibitors / Q000378:metabolism; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D001426:Bacterial Proteins; D011480:Protease Inhibitors; D054852:Small Molecule Libraries; D045726:Metalloproteases; C568073:Zmp1 protein, Mycobacterium tuberculosis; D015260:Neprilysin
Enzyme inhibitors; Metalloproteases; Tuberculosis; Virtual screening; Zmp1