Double click reaction for the acquisition of a highly potent and selective mPTPB inhibitor

Rongjun He, Zhihong Yu, Yantao He, Li Fan Zeng, Jie Xu, Li Wu, Andrea M. Gunawan, Lina Wang, Zhong Xing Jiang, Zhong-Yin Zhang

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Tuberculosis (TB), which is caused by Mycobacterium tuberculosis (Mtb), is a major worldwide threat to public health. Mycobacterium protein tyrosine phosphatase B (mPTPB) is a virulent phosphatase secreted by Mtb, which is essential for the survival and persistence of the bacterium in the host. Consequently, small-molecule inhibitors of mPTPB are expected to serve as anti-TB agents with a novel mode of action. Herein, we report the discovery of highly potent and selective mPTPB inhibitors using a novel, double Click chemistry strategy. The most potent mPTPB inhibitor from this approach possesses a Ki value of 160 nm and a >25-fold selectivity for mPTPB over 19 other protein tyrosine phosphatases (PTBs). Molecular docking study of the enzyme-inhibitor complex provides a rationale for the high potency and selectivity of the lead compound and reveals an unusual binding mode, which may guide further optimization effort.

Original languageEnglish
Pages (from-to)2051-2056
Number of pages6
JournalChemMedChem
Volume5
Issue number12
DOIs
StatePublished - Dec 3 2010

Fingerprint

Protein Tyrosine Phosphatases
Mycobacterium
Mycobacterium tuberculosis
Tuberculosis
Click Chemistry
Lead compounds
Enzyme Inhibitors
Public health
Phosphoric Monoester Hydrolases
Bacteria
Public Health
Molecules

Keywords

  • Click chemistry
  • Drug design
  • Inhibitors
  • Protein tyrosine phosphatases
  • Tuberculosis

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry
  • Molecular Medicine

Cite this

Double click reaction for the acquisition of a highly potent and selective mPTPB inhibitor. / He, Rongjun; Yu, Zhihong; He, Yantao; Zeng, Li Fan; Xu, Jie; Wu, Li; Gunawan, Andrea M.; Wang, Lina; Jiang, Zhong Xing; Zhang, Zhong-Yin.

In: ChemMedChem, Vol. 5, No. 12, 03.12.2010, p. 2051-2056.

Research output: Contribution to journalArticle

He, R, Yu, Z, He, Y, Zeng, LF, Xu, J, Wu, L, Gunawan, AM, Wang, L, Jiang, ZX & Zhang, Z-Y 2010, 'Double click reaction for the acquisition of a highly potent and selective mPTPB inhibitor', ChemMedChem, vol. 5, no. 12, pp. 2051-2056. https://doi.org/10.1002/cmdc.201000348
He, Rongjun ; Yu, Zhihong ; He, Yantao ; Zeng, Li Fan ; Xu, Jie ; Wu, Li ; Gunawan, Andrea M. ; Wang, Lina ; Jiang, Zhong Xing ; Zhang, Zhong-Yin. / Double click reaction for the acquisition of a highly potent and selective mPTPB inhibitor. In: ChemMedChem. 2010 ; Vol. 5, No. 12. pp. 2051-2056.
@article{8ed84276340348508ada6d0a8a57ff76,
title = "Double click reaction for the acquisition of a highly potent and selective mPTPB inhibitor",
abstract = "Tuberculosis (TB), which is caused by Mycobacterium tuberculosis (Mtb), is a major worldwide threat to public health. Mycobacterium protein tyrosine phosphatase B (mPTPB) is a virulent phosphatase secreted by Mtb, which is essential for the survival and persistence of the bacterium in the host. Consequently, small-molecule inhibitors of mPTPB are expected to serve as anti-TB agents with a novel mode of action. Herein, we report the discovery of highly potent and selective mPTPB inhibitors using a novel, double Click chemistry strategy. The most potent mPTPB inhibitor from this approach possesses a Ki value of 160 nm and a >25-fold selectivity for mPTPB over 19 other protein tyrosine phosphatases (PTBs). Molecular docking study of the enzyme-inhibitor complex provides a rationale for the high potency and selectivity of the lead compound and reveals an unusual binding mode, which may guide further optimization effort.",
keywords = "Click chemistry, Drug design, Inhibitors, Protein tyrosine phosphatases, Tuberculosis",
author = "Rongjun He and Zhihong Yu and Yantao He and Zeng, {Li Fan} and Jie Xu and Li Wu and Gunawan, {Andrea M.} and Lina Wang and Jiang, {Zhong Xing} and Zhong-Yin Zhang",
year = "2010",
month = "12",
day = "3",
doi = "10.1002/cmdc.201000348",
language = "English",
volume = "5",
pages = "2051--2056",
journal = "ChemMedChem",
issn = "1860-7179",
publisher = "John Wiley and Sons Ltd",
number = "12",

}

TY - JOUR

T1 - Double click reaction for the acquisition of a highly potent and selective mPTPB inhibitor

AU - He, Rongjun

AU - Yu, Zhihong

AU - He, Yantao

AU - Zeng, Li Fan

AU - Xu, Jie

AU - Wu, Li

AU - Gunawan, Andrea M.

AU - Wang, Lina

AU - Jiang, Zhong Xing

AU - Zhang, Zhong-Yin

PY - 2010/12/3

Y1 - 2010/12/3

N2 - Tuberculosis (TB), which is caused by Mycobacterium tuberculosis (Mtb), is a major worldwide threat to public health. Mycobacterium protein tyrosine phosphatase B (mPTPB) is a virulent phosphatase secreted by Mtb, which is essential for the survival and persistence of the bacterium in the host. Consequently, small-molecule inhibitors of mPTPB are expected to serve as anti-TB agents with a novel mode of action. Herein, we report the discovery of highly potent and selective mPTPB inhibitors using a novel, double Click chemistry strategy. The most potent mPTPB inhibitor from this approach possesses a Ki value of 160 nm and a >25-fold selectivity for mPTPB over 19 other protein tyrosine phosphatases (PTBs). Molecular docking study of the enzyme-inhibitor complex provides a rationale for the high potency and selectivity of the lead compound and reveals an unusual binding mode, which may guide further optimization effort.

AB - Tuberculosis (TB), which is caused by Mycobacterium tuberculosis (Mtb), is a major worldwide threat to public health. Mycobacterium protein tyrosine phosphatase B (mPTPB) is a virulent phosphatase secreted by Mtb, which is essential for the survival and persistence of the bacterium in the host. Consequently, small-molecule inhibitors of mPTPB are expected to serve as anti-TB agents with a novel mode of action. Herein, we report the discovery of highly potent and selective mPTPB inhibitors using a novel, double Click chemistry strategy. The most potent mPTPB inhibitor from this approach possesses a Ki value of 160 nm and a >25-fold selectivity for mPTPB over 19 other protein tyrosine phosphatases (PTBs). Molecular docking study of the enzyme-inhibitor complex provides a rationale for the high potency and selectivity of the lead compound and reveals an unusual binding mode, which may guide further optimization effort.

KW - Click chemistry

KW - Drug design

KW - Inhibitors

KW - Protein tyrosine phosphatases

KW - Tuberculosis

UR - http://www.scopus.com/inward/record.url?scp=78651514083&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78651514083&partnerID=8YFLogxK

U2 - 10.1002/cmdc.201000348

DO - 10.1002/cmdc.201000348

M3 - Article

C2 - 20957718

AN - SCOPUS:78651514083

VL - 5

SP - 2051

EP - 2056

JO - ChemMedChem

JF - ChemMedChem

SN - 1860-7179

IS - 12

ER -