Discovery and evaluation of novel inhibitors of mycobacterium protein tyrosine phosphatase B from the 6-hydroxy-benzofuran-5-carboxylic acid scaffold

Yantao He, Jie Xu, Zhi Hong Yu, Andrea M. Gunawan, Li Wu, Lina Wang, Zhong-Yin Zhang

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

Mycobacterium tuberculosis (Mtb) protein tyrosine phosphatase B (mPTPB) is a virulence factor secreted by the pathogen and mediates mycobacterial survival in macrophages by targeting host cell immune responses. Consequently, mPTPB represents an exciting new target to combat tuberculosis (TB) infection. We describe a medicinal chemistry oriented approach that transforms a benzofuran salicylic acid scaffold into a highly potent (IC50 = 38 nM) and selective mPTPB inhibitor (>50 fold against a large panel of PTPs). Importantly, the inhibitor is capable of reversing the altered host immune responses induced by the bacterial phosphatase and restoring the macrophage's full capacity to secrete IL-6 and undergo apoptosis in response to interferon-γ stimulation, validating the concept that chemical inhibition of mPTPB may be therapeutically useful for novel TB treatment. The study further demonstrates that bicyclic salicylic acid pharmacophores can be used to deliver PTP inhibitors with high potency, selectivity, and cellular efficacy.

Original languageEnglish
Pages (from-to)832-842
Number of pages11
JournalJournal of Medicinal Chemistry
Volume56
Issue number3
DOIs
StatePublished - Feb 14 2013

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Protein Tyrosine Phosphatases
Mycobacterium
Carboxylic Acids
Salicylic Acid
Tuberculosis
Chemical Phenomena
Macrophages
Pharmaceutical Chemistry
Virulence Factors
Mycobacterium tuberculosis
Phosphoric Monoester Hydrolases
Interferons
Inhibitory Concentration 50
Interleukin-6
Apoptosis
benzofuran
Infection

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Discovery and evaluation of novel inhibitors of mycobacterium protein tyrosine phosphatase B from the 6-hydroxy-benzofuran-5-carboxylic acid scaffold. / He, Yantao; Xu, Jie; Yu, Zhi Hong; Gunawan, Andrea M.; Wu, Li; Wang, Lina; Zhang, Zhong-Yin.

In: Journal of Medicinal Chemistry, Vol. 56, No. 3, 14.02.2013, p. 832-842.

Research output: Contribution to journalArticle

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