Exploring structural motifs necessary for substrate binding in the active site of Escherichia coli pantothenate kinase

Awuah, Emelia; Ma, Eric; Hoegl, Annabelle; Vong, Kenward; Habib, Eric; Auclair, Karine

doi:10.1016/j.bmc.2014.04.030

Cited by 13 publications

(15 citation statements)

References 36 publications

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“…In order to confirm the optimal positioning of the amide-mimicking triazole group, a compound in which the triazole ring of compound 1e is shifted two carbon atoms down the chain was designed (Table 1, compound 2). It was synthesized as previously reported (25). As expected, the antiplasmodial activity of compound 2 against asexual, blood-stage P. falciparum was significantly less than that of compound 1e, with an IC 50 of 3.5 Ϯ 1.2 M (n ϭ 3; CI ϭ 2.0 to 4.9 M, power ϭ 0.998).…”

Section: Resultsmentioning

confidence: 69%

“…2A, Table 1), previously reported as part of an investigation into the structural requirements for substrate binding to the Escherichia coli PanK (25), was identified as a more-stable derivative of N5-Pan. Based on the description of how the triazole may mimic amide bonds by Genazzani and coworkers, a closer mimic of N5-Pan would have had its triazole moiety one carbon further away from the pantoyl group than does compound 1e; however, docking studies with selected CoA-binding enzymes suggest that compound 1e might be a better mimic of N5-Pan (note that three-dimensional [3D] structures have not been reported for any of the P. falciparum CoA biosynthesis enzymes).…”

Section: Resultsmentioning

confidence: 97%

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Triazole Substitution of a Labile Amide Bond Stabilizes Pantothenamides and Improves Their Antiplasmodial Potency

Howieson

Tran

Hoegl

et al. 2016

Antimicrob Agents Chemother

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The biosynthesis of coenzyme A (CoA) from pantothenate and the utilization of CoA in essential biochemical pathways represent promising antimalarial drug targets. Pantothenamides, amide derivatives of pantothenate, have potential as antimalarials, but a serum enzyme called pantetheinase degrades pantothenamides, rendering them inactive in vivo. In this study, we characterize a series of 19 compounds that mimic pantothenamides with a stable triazole group instead of the labile amide. Two of these pantothenamides are active against the intraerythrocytic stage parasite with 50% inhibitory concentrations (IC 50 s) of ϳ50 nM, and three others have submicromolar IC 50 s. We show that the compounds target CoA biosynthesis and/or utilization. We investigated one of the compounds for its ability to interact with the Plasmodium falciparum pantothenate kinase, the first enzyme involved in the conversion of pantothenate to CoA, and show that the compound inhibits the phosphorylation of [ 14 C]pantothenate by the P. falciparum pantothenate kinase, but the inhibition does not correlate with antiplasmodial activity. Furthermore, the compounds are not toxic to human cells and, importantly, are not degraded by pantetheinase. Due to drug resistance by Plasmodium falciparum, the parasite responsible for malaria, it is vital to identify new chemotherapeutics targeting novel parasite pathways. P. falciparum does not survive its asexual red blood cell (RBC) stage without access to exogenous pantothenate (vitamin B 5 ) (1-3). Pantothenate is metabolized by five enzymes into coenzyme A (CoA), a cofactor estimated to be required by 9% of all enzymes (4). The first enzyme in the CoA biosynthetic pathway is pantothenate kinase (PanK), which catalyzes the phosphorylation of pantothenate into phosphopantothenate. Several pantothenate analogues have been shown to inhibit the growth of P. falciparum in vitro, including pantothenol (5), 801 (6), and various other analogues (7,8). Pantothenol (Fig. 1) has also been shown to possess antiplasmodial activity in vivo in a mouse model of malaria (5). Recently, pantothenamides, amides of pantothenate initially investigated for antibacterial activity (9-11), have been shown to possess potent antiplasmodial activity (12). Unfortunately, the effectiveness of pantothenamides as antiplasmodials is attenuated by pantetheinase (12), an enzyme found in human serum (13). The endogenous substrate of pantetheinase is pantetheine, which is broken down by pantetheinase into pantothenate and cysteamine (14). Pantetheinase also breaks down pantothenamides (12), including the prototypical pantothenamide, N-pentylpantothenamide (N5-Pan [ Fig. 1]). The breakdown of pantothenamides is an obstacle that needs to be overcome if these compounds are to be of any use as antimicrobial agents.There are two obvious ways by which the breakdown of pantothenamides by pantetheinase can be prevented: (i) development of a pantetheinase inhibitor that can be coadministered with the pantothenamide, a strategy recently demonstrated to b...

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Section: Resultsmentioning

confidence: 69%

Section: Resultsmentioning

confidence: 97%

Triazole Substitution of a Labile Amide Bond Stabilizes Pantothenamides and Improves Their Antiplasmodial Potency

Howieson

Tran

Hoegl

et al. 2016

Antimicrob Agents Chemother

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“…The pantothenate analogues CJ-15,801 [ 25 ], N5-trz-C1-Pan [ 26 ] and N -PE-αMe-PanAm [ 21 ], used in this study were synthesised as reported previously.…”

Section: Methodsmentioning

confidence: 99%

Mutations in the pantothenate kinase of Plasmodium falciparum confer diverse sensitivity profiles to antiplasmodial pantothenate analogues

et al. 2018

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The malaria-causing blood stage of Plasmodium falciparum requires extracellular pantothenate for proliferation. The parasite converts pantothenate into coenzyme A (CoA) via five enzymes, the first being a pantothenate kinase (PfPanK). Multiple antiplasmodial pantothenate analogues, including pantothenol and CJ-15,801, kill the parasite by targeting CoA biosynthesis/utilisation. Their mechanism of action, however, remains unknown. Here, we show that parasites pressured with pantothenol or CJ-15,801 become resistant to these analogues. Whole-genome sequencing revealed mutations in one of two putative PanK genes (Pfpank1) in each resistant line. These mutations significantly alter PfPanK activity, with two conferring a fitness cost, consistent with Pfpank1 coding for a functional PanK that is essential for normal growth. The mutants exhibit a different sensitivity profile to recently-described, potent, antiplasmodial pantothenate analogues, with one line being hypersensitive. We provide evidence consistent with different pantothenate analogue classes having different mechanisms of action: some inhibit CoA biosynthesis while others inhibit CoA-utilising enzymes.

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“…Compounds containing guanidine hydrochloride (compounds 11a ~ c ) can be synthesised by the following methods. 9a ~ 9b were prepared from the appropriate aliphatic diamine [34] (Scheme S2). Hereafter, these molecules were reacted with 1a ~ b to produce 10a ~ c .…”

Section: Resultsmentioning

confidence: 99%

Virtual Screening Guided Design, Synthesis and Bioactivity Study of Benzisoselenazolones (BISAs) on Inhibition of c-Met and Its Downstream Signalling Pathways

Zhang

Song

Wang

et al. 2019

IJMS

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c-Met is a transmembrane receptor tyrosine kinase and an important therapeutic target for anticancer drugs. In this study, we designed a small library containing 300 BISAs molecules that consisted of carbohydrates, amino acids, isothiourea, tetramethylthiourea, guanidine and heterocyclic groups and screened c-Met targeting compounds using docking and MM/GBSA. Guided by virtual screening, we synthesised a series of novel compounds and their activity on inhibition of the autophosphorylation of c-Met and its downstream signalling pathway proteins were evaluated. We found a panel of benzisoselenazolones (BISAs) obtained by introducing isothiourea, tetramethylthiourea and heterocyclic groups into the C-ring of Ebselen, including 7a, 7b, 8a, 8b and 12c (with IC50 values of less than 20 μM in MET gene amplified lung cancer cell line EBC-1), exhibited more potent antitumour activity than Ebselen by cell growth assay combined with in vitro biochemical assays. In addition, we also tested the antitumour activity of three cancer cell lines without MET gene amplification/activation, including DLD1, MDA-MB-231 and A549. The neuroblastoma SK-N-SH cells with HGF overexpression which activates MET signalling are sensitive to MET inhibitors. The results reveal that our compounds may be nonspecific multitarget kinase inhibitors, just like type-II small molecule inhibitors. Western blot analysis showed that these inhibitors inhibited autophosphorylation of c-MET, and its downstream signalling pathways, such as PI3K/AKT and MARK/ERK. Results suggest that bensoisoselenones can be used as a scaffold for the design of c-Met inhibiting drug leads, and this study opens up new possibilities for future antitumour drug design.

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Exploring structural motifs necessary for substrate binding in the active site of Escherichia coli pantothenate kinase

Cited by 13 publications

References 36 publications

Triazole Substitution of a Labile Amide Bond Stabilizes Pantothenamides and Improves Their Antiplasmodial Potency

Triazole Substitution of a Labile Amide Bond Stabilizes Pantothenamides and Improves Their Antiplasmodial Potency

Mutations in the pantothenate kinase of Plasmodium falciparum confer diverse sensitivity profiles to antiplasmodial pantothenate analogues

Virtual Screening Guided Design, Synthesis and Bioactivity Study of Benzisoselenazolones (BISAs) on Inhibition of c-Met and Its Downstream Signalling Pathways

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