Methionine aminopeptidase 2 is a key regulator of apoptotic like cell death in Leishmania donovani

Kumar, Ritesh; Tiwari, Kartikeya; Dubey, Vikash Kumar

doi:10.1038/s41598-017-00186-9

Cited by 21 publications

(10 citation statements)

References 55 publications

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“…Having observed above‐discussed hallmarks of apoptosis, we concluded apoptosis‐like death by investigating genomic DNA integrity of parasites, another major event of apoptosis . Promastigotes treated with compounds 1–3 were analyzed for internucleosomal gDNA fragmentation.…”

Section: Resultsmentioning

confidence: 99%

Design and synthesis of imidazolidinone derivatives as potent anti‐leishmanial agents by bioisosterism

Ramu

Jain

Kumar

et al. 2019

Archiv der Pharmazie

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Bioisosterism is a useful strategy in rational drug design to improve pharmacodynamic and pharmacokinetic properties of lead compounds. Imidazolidinones have been reported as potent kinase inhibitors and antileishmanial agents. In this study, bioisosteres of imidazolidinones (compounds 1-3) were evaluated for their antileishmanial properties. The modified imidazolidinones exhibited potent antileishmanial activity against extracellular as well as intracellular Leishmania donovani parasites in nanomolar concentrations. The selectivity index of these compounds on host cells was found to be more than 1000, emphasizing their specificity toward the parasite. Using SwissTargetPrediction software, we assessed the potential targets of these compounds and found MAPK as the most probable target. To in vitro validate, we developed a novel in vitro kinase assay that mimics the in vivo nature of the functional kinome. Compounds 1-3 displayed specific inhibition of parasite kinase activity accompanied by an increase in intracellular sodium levels in the parasites. This might be the effect of kinase inhibition that regulates sodium homeostasis through Na-ATPases.Finally, the compound-treated parasites underwent apoptosis-like death. This study represents bioisoterism as a novel approach for drug design to establish the structureactivity relationship, which in turn helps to improve the therapeutic activity of lead compounds. K E Y W O R D Sbioisosterism, high-throughput kinase assay, imidazolidinones, leishmaniasis, target deconvolution

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Section: Resultsmentioning

confidence: 99%

Design and synthesis of imidazolidinone derivatives as potent anti‐leishmanial agents by bioisosterism

Ramu

Jain

Kumar

et al. 2019

Archiv der Pharmazie

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“…2016 ) as well as many deep-sea fishes ( Hunt et al. 2001 ; Lin et al. 2017 ) and sharks ( Hart et al.…”

Section: Discussionmentioning

confidence: 99%

Recreated Ancestral Opsin Associated with Marine to Freshwater Croaker Invasion Reveals Kinetic and Spectral Adaptation

Nynatten

Castiglione

Gutierrez

et al. 2021

Molecular Biology and Evolution

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Rhodopsin, the light-sensitive visual pigment expressed in rod photoreceptors, is specialized for vision in dim light environments. Aquatic environments are particularly challenging for vision due to the spectrally-dependent attenuation of light, which can differ greatly in marine and freshwater systems. Among fish lineages that have successfully colonized freshwater habitats from ancestrally marine environments, croakers are known as highly visual benthic predators. In this study, we isolate rhodopsins from a diversity of freshwater and marine croakers, and find that strong positive selection in rhodopsin is associated with a marine to freshwater transition in South American croakers. In order to determine if this is accompanied by significant shifts in visual abilities, we resurrected ancestral rhodopsin sequences, and tested the experimental properties of ancestral pigments bracketing this transition using in vitro spectroscopic assays. We found the ancestral freshwater croaker rhodopsin is red-shifted relative to its marine ancestor, with mutations that recapitulate ancestral amino acid changes along this transitional branch resulting in faster kinetics that are likely to be associated with more rapid dark adaptation. This could be quite advantageous in freshwater due to the red-shifted spectrum and relatively narrow interface and frequent transitions between bright and dim light environments. This study is the first to experimentally demonstrate that positively selected substitutions in ancestral visual pigments alter protein function to freshwater visual environments following a transition from an ancestrally marine state, and provides insight into the molecular mechanisms underlying some of the physiological changes associated with this major habitat transition.

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“…The metalloprotease, methionine amino peptidase (MetAP), has been reported as a novel therapeutic target for infectious diseases. [3][4][5][6][7][8][9][10][11] It has been validated as a target for various infectious diseases caused by methicillinresistant Staphylococcus aureus and Escherichia coli, 3 Mycobacterium tuberculosis (Mtb), [4][5][6][7] Cryptosporidium parvum, 8 Plasmodium falciparum, 9 Leishmania donovani, 10 Enterococcus faecalis, 11,12 Rickettsia prowazekii, 13 and Acinetobacter baumannii. 14 It has also been investigated as a potential therapeutic target for several other diseases including cancer and rheumatoid arthritis.…”

Section: Introductionmentioning

confidence: 99%

<p>Pre-Clinical Pharmacokinetics, Tissue Distribution and Physicochemical Studies of CLBQ14, a Novel Methionine Aminopeptidase Inhibitor for the Treatment of Infectious Diseases</p>

Ekpenyong¹,

Gao²,

Ma³

et al. 2020

DDDT

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Introduction: CLBQ14, a derivative of 8-hydroxyquinoline, exerts its chemotherapeutic effect by inhibiting methionine aminopeptidase (MetAP), the enzyme responsible for the post-translational modification of several proteins and polypeptides. MetAP is a novel target for infectious diseases. CLBQ14 is selective and highly potent against replicating and latent Mycobacterium tuberculosis making it an appealing lead for further development. Methods: The physicochemical properties (solubility, pH stability and lipophilicity), in vitro plasma stability and metabolism, pre-clinical pharmacokinetics, plasma protein binding and tissue distribution of CLBQ14 in adult male Sprague-Dawley rats were characterized. Results: At room temperature, CLBQ14 is practically insoluble in water (<0.07 mg/mL) but freely soluble in dimethyl acetamide (>80 mg/mL); it has a log P value of 3.03 ± 0.04. CLBQ14 exhibits an inverse Z-shaped pH decomposition profile; it is stable at acidic pH but is degraded at a faster rate at basic pH. It is highly bound to plasma proteins (>91%), does not partition to red blood cells (B/P ratio: 0.83 ± 0.03), and is stable in mouse, rat, monkey and human plasma. CLBQ14 exhibited a bi-exponential pharmacokinetics after intravenous administration in rats, bioavailability of 39.4 and 90.0%, respectively from oral and subcutaneous route. We observed a good correlation between predicted and observed rat clearance, 1.90 ± 0.17 L/kg/h and 1.67 ± 0.08 L/kg/h, respectively. Human hepatic clearance predicted from microsomal stability data and from the single species scaling were 0.80 L/hr/kg and 0.69 L/h/kg, respectively. CLBQ14 is extensively distributed in rats; following a 5 mg/kg intravenous administration, lowest and highest concentrations of 15.6 ± 4.20 ng/g of heart and 405.9 ± 77.11 ng/g of kidneys, respectively, were observed. In vitro CYP reaction phenotyping demonstrates that CLBQ14 is metabolized primarily by CYP 1A2. Conclusion: CLBQ14 possess appealing qualities of a drug candidate. The studies reported herein are imperative to the development of CLBQ14 as a new chemical entity for infectious diseases.

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Methionine aminopeptidase 2 is a key regulator of apoptotic like cell death in Leishmania donovani

Cited by 21 publications

References 55 publications

Design and synthesis of imidazolidinone derivatives as potent anti‐leishmanial agents by bioisosterism

Design and synthesis of imidazolidinone derivatives as potent anti‐leishmanial agents by bioisosterism

Recreated Ancestral Opsin Associated with Marine to Freshwater Croaker Invasion Reveals Kinetic and Spectral Adaptation

<p>Pre-Clinical Pharmacokinetics, Tissue Distribution and Physicochemical Studies of CLBQ14, a Novel Methionine Aminopeptidase Inhibitor for the Treatment of Infectious Diseases</p>

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