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

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

Dipartimento di Scienze del Farmaco

Risultato della ricerca: Contributo su rivista › Articolo in rivista › peer review

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

Lingua originale	Inglese
pagine (da-a)	2508-2511
Numero di pagine	4
Rivista	Bioorganic and Medicinal Chemistry Letters
Volume	24
Numero di pubblicazione	11
DOI	https://doi.org/10.1016/j.bmcl.2014.04.004
Stato di pubblicazione	Pubblicato - 1 giu 2014

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10.1016/j.bmcl.2014.04.004

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title = "Discovery of the first potent and selective Mycobacterium tuberculosis Zmp1 inhibitor",

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",

author = "Mattia Mori and Francesca Moraca and Davide Deodato and Ferraris, \{Davide M.\} and Petra Selchow and Peter Sander and Menico Rizzi and Maurizio Botta",

note = "Funding Information: This work was partially supported by the European Union FP7 program (Project SysteMTb HEALTH-F4-2010-241587). Research in the laboratory of P.S. is supported by Swiss National Science Foundation , EU NewTBVac (No. 241 745 ) and Tuberculosis Vaccine Initiative (TBVI). ",

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doi = "10.1016/j.bmcl.2014.04.004",

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AU - Mori, Mattia

AU - Moraca, Francesca

AU - Deodato, Davide

AU - Ferraris, Davide M.

AU - Selchow, Petra

AU - Sander, Peter

AU - Rizzi, Menico

AU - Botta, Maurizio

N1 - Funding Information: This work was partially supported by the European Union FP7 program (Project SysteMTb HEALTH-F4-2010-241587). Research in the laboratory of P.S. is supported by Swiss National Science Foundation , EU NewTBVac (No. 241 745 ) and Tuberculosis Vaccine Initiative (TBVI).

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N2 - 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.

AB - 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.

KW - Enzyme inhibitors

KW - Metalloproteases

KW - Tuberculosis

KW - Virtual screening

KW - Zmp1

UR - https://www.scopus.com/pages/publications/84899968464

U2 - 10.1016/j.bmcl.2014.04.004

DO - 10.1016/j.bmcl.2014.04.004

M3 - Article

SN - 0960-894X

VL - 24

SP - 2508

EP - 2511

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 11

ER -

Discovery of the first potent and selective Mycobacterium tuberculosis Zmp1 inhibitor

Abstract

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