Fragment-Based Substrate Activity Screening Method for the Identification of Potent Inhibitors of the<i>Mycobacterium tuberculosis</i>Phosphatase PtpB

Soellner, Matthew B.; Rawls, Katherine A.; Grundner, Christoph; Alber, Tom; Ellman, Jonathan A.

doi:10.1021/ja0727520

Cited by 105 publications

(100 citation statements)

References 23 publications

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“…Moreover, since mPTPB is secreted into the cytosol of host macrophages, drugs targeting mPTPB are not required to penetrate the waxy mycobacterial cell wall. Accordingly, there is increasing interest in developing mPTPB inhibitors (17)(18)(19)(20)(21). However, the common architecture of the PTP active site (i.e., pTyr-binding pocket) poses a significant challenge for the acquisition of selective PTP inhibitors.…”

Section: Resultsmentioning

confidence: 99%

Targeting mycobacterium protein tyrosine phosphatase B for antituberculosis agents

Zhou¹,

He²,

Zhang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

209

205

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Protein tyrosine phosphatases are often exploited and subverted by pathogenic bacteria to cause human diseases. The tyrosine phosphatase mPTPB from Mycobacterium tuberculosis is an essential virulence factor that is secreted by the bacterium into the cytoplasm of macrophages, where it mediates mycobacterial survival in the host. Consequently, there is considerable interest in understanding the mechanism by which mPTPB evades the host immune responses, and in developing potent and selective mPTPB inhibitors as unique antituberculosis (antiTB) agents. We uncovered that mPTPB subverts the innate immune responses by blocking the ERK1/2 and p38 mediated IL-6 production and promoting host cell survival by activating the Akt pathway. We identified a potent and selective mPTPB inhibitor I-A09 with highly efficacious cellular activity, from a combinatorial library of bidentate benzofuran salicylic acid derivatives assembled by click chemistry. We demonstrated that inhibition of mPTPB with I-A09 in macrophages reverses the altered host immune responses induced by the bacterial phosphatase and prevents TB growth in host cells. The results provide the necessary proof-of-principle data to support the notion that specific inhibitors of the mPTPB may serve as effective antiTB therapeutics.combinatorial chemistry | pathogen-host interaction | phosphatase inhibitor | signaling mechanism

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Section: Resultsmentioning

confidence: 99%

Targeting mycobacterium protein tyrosine phosphatase B for antituberculosis agents

Zhou¹,

He²,

Zhang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

209

205

View full text Add to dashboard Cite

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“…Recently some new targets such as signaling kinase inhibitors have been investigated. The survival of M. tuberculosis against the macrophage phagocytosis relies not only on a thick cell wall but also on many mycobacterial kinases and phosphatases which disrupt the host-cell defence mechanism against parasitism (92)(93)(94). Histidine kinase is the focus for the specific inhibition of two component signal transduction system in mycobacteria (95)(96)(97)(98).…”

Section: 24-benzothiadiazinesmentioning

confidence: 99%

Efforts Towards the Development of New Antitubercular Agents: Potential for Thiolactomycin Based Compounds

et al. 2008

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Development of new chemotherapeutic drugs is the need of the hour to improve tuberculosis control, particularly in the developing world. In the last fourty years no new compound has been brought to the market for the treatment of tuberculosis. However, in recent years there is an enhanced activity in the research and development of new drugs for TB. Some compounds are presently in clinical development, while others are being investigated pre-clinically in an attempt to explore new molecules for the target based treatment of TB. Simultaneously some new targets are being identified and validated for their practical usefulness. Structures based on thiolactomycin could have considerable potential in the development of target based anti-TB agents. The present review provides an overview of the drugs that are being clinically used and the compounds that are in advanced stages of clinical as well as preclinical studies. We have also attempted to highlight the efforts that are being made in the development of new molecules based on thiolactomycin as lead compound, including studies from this laboratory.

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“…[12] In addition, dynamic substrate enhancement, as demonstrated here, supports the recent finding of Ellman's group that screening substrate libraries can be useful for the development of improved enzyme inhibitors. [13] Protein tyrosine phosphatases (PTPs) are key regulators in living systems and thus are attractive drug targets. The development of potent, selective PTP inhibitors has been a difficult challenge mainly due to the high homology of the phosphotyrosine substrate pockets.…”

Section: Introductionmentioning

confidence: 99%

Dynamic Substrate Enhancement for the Identification of Specific, Second‐Site‐Binding Fragments Targeting a Set of Protein Tyrosine Phosphatases

2011

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Protein tyrosine phosphatases (PTPs) are key regulators in living systems and thus are attractive drug targets. The development of potent, selective PTP inhibitors has been a difficult challenge mainly due to the high homology of the phosphotyrosine substrate pockets. Here, a strategy of dynamic substrate enhancement is described targeting the secondary binding sites of PTPs. By screening four different PTPs from bacterial (MptpA) and human origin (PTP1B, HePtp, Shp2) with this assay, specific fragments were identified. One highly specific fragment that binds to the secondary site of Mycobacterium tuberculosis protein tyrosine phosphatase A (MptpA) was characterized in order to validate the assay concept. Finally by covalently linking the secondary fragment to a phosphotyrosine mimetic, a moderately active but highly specific inhibitor of MptpA was obtained.

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Fragment-Based Substrate Activity Screening Method for the Identification of Potent Inhibitors of theMycobacterium tuberculosisPhosphatase PtpB

Cited by 105 publications

References 23 publications

Targeting mycobacterium protein tyrosine phosphatase B for antituberculosis agents

Targeting mycobacterium protein tyrosine phosphatase B for antituberculosis agents

Efforts Towards the Development of New Antitubercular Agents: Potential for Thiolactomycin Based Compounds

Dynamic Substrate Enhancement for the Identification of Specific, Second‐Site‐Binding Fragments Targeting a Set of Protein Tyrosine Phosphatases

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