Brunsvicamides A−C:  Sponge-Related Cyanobacterial Peptides with <i>Mycobacterium </i><i>tuberculosis</i> Protein Tyrosine Phosphatase Inhibitory Activity

Müller, Daniela; Krick, Anja; Kehraus, Stefan; Mehner, Christian; Hart, Michael W.; Küpper, Frithjof C.; Saxena, Krishna; Prinz, Heino; Schwalbe, Harald; Janning, Petra; Waldmann, Herbert; König, Gabriele M.

doi:10.1021/jm060327w

Cited by 75 publications

(64 citation statements)

References 36 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

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“…These, especially Brunsvicamide B and C (Figure 1), were shown to target protein tyrosine phosphatase B (MptpB) which is an essential virulence factor of mycobacterial species. The activity of these compounds were successfully assessed against a range of protein phosphatases where MptpB showed an IC 50 of 7.3 µM [35]. The characterization of MptpB as the target directly led to the identification of novel synthetic inhibitors of this protein using high-throughput screens [36].…”

Section: Biochemical Approachesmentioning

confidence: 99%

Target Discovery Focused Approaches to Overcome Bottlenecks in the Exploitation of Antimycobacterial Natural Products

et al. 2018

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Tuberculosis is a major global health hazard. The search for new antimycobacterials has focused on such as screening combinational chemistry libraries or designing chemicals to target prede ned pockets of essential bacterial proteins. The relative ineffectiveness of these has led to a reappraisal of natural products for new antimycobacterial drug leads. However, progress has been limited, we suggest through a failure in many cases to de ne the drug target and optimize the hits using this information. We highlight methods of target discovery needed to develop a drug into a candidate for clinical trials. We incorporate these into suggested analysis pipelines which could inform the research strategies to accelerate the development of new drug leads from natural products. Natural products: moving back to the forefront of antimycobacterial target discovery Tuberculosis (TB) is the world's leading cause of death from infectious disease, causing an estimated 1.4 million deaths in 2015 [1]. This effectively represents a reverse of trends seen during the middle years of the 20th century when antibiotics, developed from the 1940s, appeared to be effective in controlling the disease. However, over the last two decades TB is again a major public health hazard with the appearance of drug-resistant strains of TB, multidrug-resistant TB (MDR-TB), extensively drug-resistant TB (XDR-TB) and more recently strains resistant to all the antitubercular chemotherapies [2]. This situation has arisen for a great extent due to the complex drug therapy regime used for TB which reduces patient compliance and adherence to prescribed medication. Thus, antitubercular chemotherapy comprises at least a 6-month drug regimen involving an initial 2-month phase of four agents (isoniazid, rifampicin, pyrazinamide and ethambutol) followed by an additional 4 months with isoniazid and rifampicin [3,4].MDR-TB is resistant to both ifampicin and isoniazid, the most effective antituberculous drugs. XDR-TB strains are resistant to at least rifampicin and isoniazid but also fluoroquinolones and to, at least, one of the injectable drugs; capreomycin, kanamycin or amikacin. Treatment of MDR-TB consists of a 2-year therapy with a combination of four to six first-and second-line antitubercular drugs [5]. TB control is therefore contingent on the development of new drugs and in the past decade there have been major efforts made in this area. There is also a need for new drugs that act quickly, giving fewer opportunities for the TB-causing organism to develop resistance. Any new drugs also need to be inexpensive to produce, so that it can be widely adopted in countries outside of the first world. Due to renewed research and development efforts, bedaquiline, a diarylquinolone, became the first anti-TB drug approved by the US FDA in more than 40 years [6]. Additionally, innovative methodologies have allowed the development of more effective therapies, the 'revitalization' of old drugs, re-use of drugs in different contexts, and the reduction of drugs rejected due to...

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“…Synthesis of brunsvicamide A (1) and seven stereochemical analogues (28)(29)(30)(31)(32)(33)(34). For the stereochemical assignments see Table 1. www.chembiochem.org material retrieved by isolation, [10] neither synthetic 1 nor 28-34 gave any measurable inhibition of MptpB up to a concentration of 100 mm with the substrates pNPP [20] or DiFUMP [21] (see the Supporting Information for details). Currently we reason that an impurity might be responsible for the inhibitory activity of the material isolated from the producing organism.…”

Section: Investigation Of Phosphatase Inhibitionmentioning

confidence: 99%

“…[10] Five amino acids form the cyclic backbones of the these branched hexapeptides through a d-lysine side chain. The sixth amino acid is found linked to a urea moiety at the a-amino group of the d-lysine.…”

Section: Introductionmentioning

confidence: 99%

“…[17] Moreover, the NP isolates interfered with the function of tyrosine phosphatase B from Mycobacterium tuberculosis (MptpB) at micromolar concentrations. [10] In general, protein phosphatases act in concert with protein kinases to control the state of protein phosphorylation, and thereby regulate enzymatic activity and modulate interactions between proteins. [18] We have recently reported the correct stereochemistry of BVA A (1) from a solid-phase-based total synthesis.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and Structure–Activity Correlation of a Brunsvicamide‐Inspired Cyclopeptide Collection

et al. 2009

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Cyanobacterial cyclopeptides: A series of analogues of the cyanobacterial cyclopeptide brunsvicamide A was prepared by effective solid-support-based total synthesis. Variations in stereochemistry revealed the importance of the D-lysine and the L-isoleucine residues for the substrate-competitive inhibitory activity of brunsvicamide A against carboxypeptidase A. The brunsvicamides are modified cyclopeptides from cyanobacteria, cyclised through the epsilon-amino group of a D-lysine unit. They are functionalised with urea groups and show potent carboxypeptidase inhibitory activities. In order to unravel the structural parameters that determine their activities, a collection of brunsvicamide analogues with varied amino acid structures and stereochemistries was synthesised by a combined solution- and solid-phase approach. Biochemical investigation of the compound collection for carboxypeptidase A inhibition revealed that the presence of D-lysine and L-isoleucine in the urea section is important for inhibition. It was found that brunsvicamide A is a substrate-competitive inhibitor of carboxypeptidase A. These findings are in agreement with the substrate specificity of the enzyme and were rationalised by computational studies, which showed the high relevance of the lysine stereochemistry for inhibitory activity.

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Brunsvicamides A−C: Sponge-Related Cyanobacterial Peptides with Mycobacterium tuberculosis Protein Tyrosine Phosphatase Inhibitory Activity

Cited by 75 publications

References 36 publications

Targeting mycobacterium protein tyrosine phosphatase B for antituberculosis agents

Targeting mycobacterium protein tyrosine phosphatase B for antituberculosis agents

Target Discovery Focused Approaches to Overcome Bottlenecks in the Exploitation of Antimycobacterial Natural Products

Synthesis and Structure–Activity Correlation of a Brunsvicamide‐Inspired Cyclopeptide Collection

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