Structural Basis for Selective Inhibition of Mycobacterium tuberculosis Protein Tyrosine Phosphatase PtpB

Grundner, Christoph; Perrin, Dominique; Huijsduijnen, Rob Hooft van; Swinnen, Dominique; Gonzalez, Jérome; Gee, Christine L.; Wells, Timothy N.C.; Alber, Tom

doi:10.1016/j.str.2007.03.003

Cited by 86 publications

(90 citation statements)

References 25 publications

(29 reference statements)

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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.

216

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.

216

205

View full text Add to dashboard Cite

show abstract

“…Grundner et al, using scaffolds from which inhibitors of eukaryotic Tyr phosphatases had been developed, identified a competitive inhibitor of PtpB with IC 50 of 0.44 μM, with good selectivity versus several human tyrosine phosphatases ( 112 ). Crystal structure analysis of this compound in complex with PtpB demonstrated conformational changes and key residues that may guide further inhibitor development.…”

Section: Tuberculosis Stpks and Phosphatases As Potential Drug Tarmentioning

confidence: 99%

Mycobacterium tuberculosis Serine/Threonine Protein Kinases

Prisic

Husson

2014

Microbiol Spectr

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The Mycobacterium tuberculosis genome encodes 11 serine/threonine protein kinases (STPKs). A similar number of two-component systems are also present, indicating that these two signal transduction mechanisms are both important in the adaptation of this bacterial pathogen to its environment. The M. tuberculosis phosphoproteome includes hundreds of Ser- and Thr-phosphorylated proteins that participate in all aspects of M. tuberculosis biology, supporting a critical role for the STPKs in regulating M. tuberculosis physiology. Nine of the STPKs are receptor type kinases, with an extracytoplasmic sensor domain and an intracellular kinase domain, indicating that these kinases transduce external signals. Two other STPKs are cytoplasmic and have regulatory domains that sense changes within the cell. Structural analysis of some of the STPKs has led to advances in our understanding of the mechanisms by which these STPKs are activated and regulated. Functional analysis has provided insights into the effects of phosphorylation on the activity of several proteins, but for most phosphoproteins the role of phosphorylation in regulating function is unknown. Major future challenges include characterizing the functional effects of phosphorylation for this large number of phosphoproteins, identifying the cognate STPKs for these phosphoproteins, and determining the signals that the STPKs sense. Ultimately, combining these STPK-regulated processes into larger, integrated regulatory networks will provide deeper insight into M. tuberculosis adaptive mechanisms that contribute to tuberculosis pathogenesis. Finally, the STPKs offer attractive targets for inhibitor development that may lead to new therapies for drug-susceptible and drug-resistant tuberculosis.

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“…In fact, as has been demonstrated, prioritized sets chosen based on the screening of compounds synthesized for a human target (actives and inactives), for which an ortholog exists in the target organism, can be extremely profitable in rapidly identifying actives and, furthermore addresses upfront the issue of selectivity. Naturally it is hoped that such screening of compounds made for human targets that have Plasmodium orthologs will deliver series that are potent and selective for the parasite over the host [133].…”

Section: Ortholog Screeningmentioning

confidence: 99%

The State of the Art in Anti-Malarial Drug Discovery and Development

Burrows

Chibale²,

Wells

2011

CTMC

145

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Malaria is one of the most prevalent and devastating infectious diseases of our time. Yet, unfortunately, apart from artemisinin combination therapies there are relatively few effective treatments for Plasmodium falciparum and only one treatment for the radical cure of Plasmodium vivax. Novel classes of antimalarial medicines are urgently needed given the long-term inevitability of resistance to current therapies and the need for drugs that are well tolerated by all. This review summarises the antimalarials developed and registered thus far, as well as describing some of the new small molecule therapy approaches being developed as a contribution towards the malaria eradication agenda.

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Structural Basis for Selective Inhibition of Mycobacterium tuberculosis Protein Tyrosine Phosphatase PtpB

Cited by 86 publications

References 25 publications

Targeting mycobacterium protein tyrosine phosphatase B for antituberculosis agents

Targeting mycobacterium protein tyrosine phosphatase B for antituberculosis agents

Mycobacterium tuberculosis Serine/Threonine Protein Kinases

The State of the Art in Anti-Malarial Drug Discovery and Development

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