Design and Synthesis of Inhibitors of Plasmodium falciparum N-Myristoyltransferase, A Promising Target for Antimalarial Drug Discovery

Zhiyong Yu; James A. Brannigan; David K. Moss; A. Marek Brzozowski; Anthony J. Wilkinson; Anthony A. Holder; Edward W. Tate; Robin J. Leatherbarrow

doi:10.1021/jm301160h

Design and Synthesis of Inhibitors of Plasmodium falciparum N-Myristoyltransferase, A Promising Target for Antimalarial Drug Discovery

Zhiyong Yu, James A. Brannigan, David K. Moss, A. Marek Brzozowski, Anthony J. Wilkinson, Anthony A. Holder, Edward W. Tate^*, Robin J. Leatherbarrow

^*Corresponding author for this work

Chemistry

Research output: Contribution to journal › Article › peer-review

Abstract

Design of inhibitors for N-myristoyltransferase (NMT), an enzyme responsible for protein trafficking in Plasmodium falciparum, the most lethal species of parasites that cause malaria, is described. Chemistry-driven optimization of compound 1 from a focused NMT inhibitor library led to the identification of two early lead compounds 4 and 25, which showed good enzyme and cellular potency and excellent selectivity over human NMT. These molecules provide a valuable starting point for further development.

Original language	English
Pages (from-to)	8879-8890
Number of pages	12
Journal	JOURNAL OF MEDICINAL CHEMISTRY
Volume	55
Issue number	20
Early online date	3 Oct 2012
DOIs	https://doi.org/10.1021/jm301160h
Publication status	Published - 25 Oct 2012

Keywords

ESSENTIAL ENZYME
MECHANISM
MALARIA
IDENTIFICATION
SELECTIVE INHIBITORS
MYRISTOYL-COA
BENZOFURANS
ADP-RIBOSYLATION FACTOR
STARTING POINTS
CANDIDA-ALBICANS

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10.1021/jm301160h

http://pubs.acs.org/doi/abs/10.1021/jm301160h

Cite this

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title = "Design and Synthesis of Inhibitors of Plasmodium falciparum N-Myristoyltransferase, A Promising Target for Antimalarial Drug Discovery",

abstract = "Design of inhibitors for N-myristoyltransferase (NMT), an enzyme responsible for protein trafficking in Plasmodium falciparum, the most lethal species of parasites that cause malaria, is described. Chemistry-driven optimization of compound 1 from a focused NMT inhibitor library led to the identification of two early lead compounds 4 and 25, which showed good enzyme and cellular potency and excellent selectivity over human NMT. These molecules provide a valuable starting point for further development.",

keywords = "ESSENTIAL ENZYME, MECHANISM, MALARIA, IDENTIFICATION, SELECTIVE INHIBITORS, MYRISTOYL-COA, BENZOFURANS, ADP-RIBOSYLATION FACTOR, STARTING POINTS, CANDIDA-ALBICANS",

author = "Zhiyong Yu and Brannigan, {James A.} and Moss, {David K.} and Brzozowski, {A. Marek} and Wilkinson, {Anthony J.} and Holder, {Anthony A.} and Tate, {Edward W.} and Leatherbarrow, {Robin J.}",

year = "2012",

month = oct,

day = "25",

doi = "10.1021/jm301160h",

language = "English",

volume = "55",

pages = "8879--8890",

journal = "JOURNAL OF MEDICINAL CHEMISTRY",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "20",

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TY - JOUR

T1 - Design and Synthesis of Inhibitors of Plasmodium falciparum N-Myristoyltransferase, A Promising Target for Antimalarial Drug Discovery

AU - Yu, Zhiyong

AU - Brannigan, James A.

AU - Moss, David K.

AU - Brzozowski, A. Marek

AU - Wilkinson, Anthony J.

AU - Holder, Anthony A.

AU - Tate, Edward W.

AU - Leatherbarrow, Robin J.

PY - 2012/10/25

Y1 - 2012/10/25

N2 - Design of inhibitors for N-myristoyltransferase (NMT), an enzyme responsible for protein trafficking in Plasmodium falciparum, the most lethal species of parasites that cause malaria, is described. Chemistry-driven optimization of compound 1 from a focused NMT inhibitor library led to the identification of two early lead compounds 4 and 25, which showed good enzyme and cellular potency and excellent selectivity over human NMT. These molecules provide a valuable starting point for further development.

AB - Design of inhibitors for N-myristoyltransferase (NMT), an enzyme responsible for protein trafficking in Plasmodium falciparum, the most lethal species of parasites that cause malaria, is described. Chemistry-driven optimization of compound 1 from a focused NMT inhibitor library led to the identification of two early lead compounds 4 and 25, which showed good enzyme and cellular potency and excellent selectivity over human NMT. These molecules provide a valuable starting point for further development.

KW - ESSENTIAL ENZYME

KW - MECHANISM

KW - MALARIA

KW - IDENTIFICATION

KW - SELECTIVE INHIBITORS

KW - MYRISTOYL-COA

KW - BENZOFURANS

KW - ADP-RIBOSYLATION FACTOR

KW - STARTING POINTS

KW - CANDIDA-ALBICANS

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U2 - 10.1021/jm301160h

DO - 10.1021/jm301160h

M3 - Article

SN - 0022-2623

VL - 55

SP - 8879

EP - 8890

JO - JOURNAL OF MEDICINAL CHEMISTRY

JF - JOURNAL OF MEDICINAL CHEMISTRY

IS - 20

ER -

Design and Synthesis of Inhibitors of Plasmodium falciparum N-Myristoyltransferase, A Promising Target for Antimalarial Drug Discovery

Abstract

Keywords

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N-Myristol Transferase as a drug target for anti-malarial therapy

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Design and Synthesis of Inhibitors of Plasmodium falciparum N-Myristoyltransferase, A Promising Target for Antimalarial Drug Discovery

Abstract

Keywords

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N-Myristol Transferase as a drug target for anti-malarial therapy

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