Targeting Acidic Mammalian chitinase Is Effective in Animal Model of Asthma

Mazur, Marzena; Olczak, Jacek; Olejniczak, Sylwia; Koralewski, Robert; Czestkowski, Wojciech; Jędrzejczak, Anna; Gołąb, Jakub; Dzwonek, Karolina; Dymek, Barbara; Sklepkiewicz, Piotr; Zagożdżon, Agnieszka; Noonan, Tom; Mahboubi, Keyvan; Conway, Bruce R.; Sheeler, Ryan; Beckett, Paul; Hungerford, William; Podjarny, A.; Mitschler, A.; Cousido-Siah, A.; Fadel, Firas; Gołębiowski, Adam

doi:10.1021/acs.jmedchem.7b01051

Cited by 27 publications

(58 citation statements)

References 30 publications

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“…Among the 1,2,4-triazoles, 3(5)-amino-1,2,4-triazoles were recently reported to be potent inhibitors of kinases, 7 lysine-specic demethylase 1, 8 and acidic mammalian chitinase. 9 Additionally, 3(5)amino-1,2,4-triazoles are also known as important building blocks for the construction of bioactive triazole-fused heterocycles. 10 Due to practical signicance of 3(5)-amino-1,2,4-triazoles, there is an ongoing demand for new efficient methods of their synthesis.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of 3-(5-amino-1H-1,2,4-triazol-3-yl)propanamides and their tautomerism

et al. 2018

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Section: Introductionmentioning

confidence: 99%

Synthesis of 3-(5-amino-1H-1,2,4-triazol-3-yl)propanamides and their tautomerism

et al. 2018

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“…These changes correlated with the decrease of chitinolytic activity in BALF. 66 Another selective AMCase inhibitor also reduced allergic inflammation (eosinophilia) but its application was associated with unexpected serious side effects, including neutrophilia, an increase in macrophage inflammatory protein-1 alpha (MIP-1α) secretion and alterations in airway remodeling genes (resulting in increased procollagen I, matrixmetalloprotease-12 (MMP-12), and Ym1 production). 67 It has to be determined whether these serious adverse events were directly drug-induced or were the result of the altered eosinophil/neutrophil balance.…”

Section: Chitinases and Clps In Animal Models Of Asthmamentioning

confidence: 99%

“…121 The results of recent studies that evaluated the efficacy of AMCase and CHIT1 inhibitors in animal models of asthma seem to be promising. 66,122 A better understanding of the physiological activity of chitinases and chitinase-like proteins could accelerate the future development of chitinase-specific therapeutic agents in obstructive lung diseases. Abbreviations: AVP, arginine-vasopressin; COPD, chronic obstructive pulmonary disease; DM2, diabetes mellitus type 2; GM-CSF, granulocyte-macrophage colonystimulating factor; IFN-γ, interferon-gamma; IL, interleukin; PTHrP, parathyroid hormone-related protein; TACE, TNF-α-converting enzyme; TLR, Toll-like receptor; TNFα, tumor necrosis factor α.…”

Section: Perspectivesmentioning

confidence: 99%

Chitinases and Chitinase-Like Proteins in Obstructive Lung Diseases – Current Concepts and Potential Applications

Przysucha¹,

Górska²,

Krenke³

2020

COPD

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Chitinases, enzymes that cleave chitin's chain to low molecular weight chitooligomers, are widely distributed in nature. Mammalian chitinases belong to the 18-glycosyl-hydrolase family and can be divided into two groups: true chitinases with enzymatic activity (AMCase and chitotriosidase) and chitinase-like proteins (CLPs) molecules which can bind to chitin or chitooligosaccharides but lack enzymatic activity (eg, YKL-40). Chitinases are thought to be part of an innate immunity against chitin-containing parasites and fungal infections. Both groups of these hydrolases are lately evaluated also as chemical mediators or biomarkers involved in airway inflammation and fibrosis. The aim of this article is to present the current knowledge on the potential role of human chitinases and CLPs in the pathogenesis, diagnosis, and course of obstructive lung diseases. We also assessed the potential role of chitinase and CLPs inhibitors as therapeutic targets in chronic obstructive pulmonary disease and asthma.

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“…Melalui mekanisme penghambatan reseptor human chitotriosidase-1 (hCHIT1), native ligand ini menunjukkan efek anti-inflamasi yang signifikan pada dosis 30 mg/Kg p.o. (Mazur et al, 2018).…”

Section: Pendahuluanunclassified

“…Data struktur reseptor kristal 3D yang digunakan untuk analisis molecular docking diperoleh dari Protein Data Bank (PDB) pada situs http://www.rscb.org/pdb/ dengan kode PDB ID 5NRA. Reseptor ini digunakan untuk memprediksi aktivitas anti-asma yang dinamakan reseptor human chitotriosidase-1 (hCHIT1) (Mazur et al, 2018).…”

Section: Metode Penelitian Materialsunclassified

Virtual Screening Kandungan Senyawa Kipas Laut (Gorgonia mariae) sebagai Anti-Asma

2020

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ABSTRAK. Kipas laut (Gorgonia mariae) telah digunakan masyarakat Maluku secara turun temurun sebagai obat asma. Kandungan metabolit sekunder yang paling dominan dalam kipas laut adalah sterol, dimana memiliki aktivitas terapi melalui efek sinergisme antara senyawa metabolit dengan polivalent activity. Pengujian kipas laut sebagai anti-asma belum pernah dilaporkan sebelumnya. Oleh karena itu, perlu dilakukan virtual screening menggunakan metode in silico pada komponen sterol kipas laut sebagai tahap awal dalam menentukan efektivitas terapi anti-asma dengan memprediksi nilai ikatan energi bebas (ΔG), konstanta inhibisi (Ki), dan interaksi residu asam amino menggunakan Autodock Tools 4.2 dan Discovery Studio 2016 Client®. Keamanan dan efektivitas kandidat obat dievaluasi menggunakan parameter dari Lipinski Rule of Five dan pre-ADMET. Hasil penelitian menunjukkan bahwa konstanta inhibisi dan ikatan energi bebas (Ki; ΔG) dari komponen senyawa kipas laut dapat diurutkan secara potensial yaitu 4,24-dimetil kolestanol (0,809; -12,40) > 24-metil-22-dehidrokolesterol (0,864; -12,36) > 23-demetil gorgosterol (1,74; -11,95) > 4,24-dimetil-22-dehidrokolestanol (1,89; -11,90). Residu asam amino yang berperan penting dalam aktivitas inhibisi hCHIT1 adalah 213-ASP. Semua komponen senyawa uji memiliki nilai log P lebih dari 5 yang menunjukkan bahwa kelarutan dan toksisitas perlu diperhatikan. Evaluasi distribusi pre-ADMET berdasarkan nilai dari pengikatan protein plasma menunjukan bahwa senyawa uji dapat berdifusi menembus membran plasma dan berinteraksi sesuai target farmakologi. Selain itu, hasil parameter uji toksisitas menunjukkan bahwa senyawa 23-demetil gorgosterol dan 4,24-dimetil-22-dehidrokolestanol memiliki potensi sebagai anti-asma.ABSTRACT. Virtual Screening of the Compounds in Gorgonians (Gorgonia mariae) as anti-asthma. The people of Maluku have used Kipas laut (G. mariae) for generations as an asthma medicine. The secondary metabolite that is most dominant in kipas laut is sterols, which have therapeutic activity through the synergistic effect between metabolite compounds and polyvalent activity. Anti-asthma activity of kipas laut has never been reported. Therefore, it is necessary to do virtual screening using the in silico method on the sterol component of kipas laut as a first step in determining the effectiveness of anti-asthma therapy by predicting the value of free energy bonds (ΔG), constant inhibition (Ki), and interactions of amino acid residues using Autodock Tools 4.2 and Discovery Studio 2016 Client®. The effectiveness and safety of prospective drugs are evaluated using the Lipinski Rule of Five and pre-ADMET. The results showed that the value of inhibition constants and free energy bonds (Ki; ΔG) on the compound of kipas laut that was potentially sorted was 4.24-dimethyl cholestanol (0.809; -12.40) > 24-methyl-22-dehydrocholesterol (0.864; -12.36) > 23-demethyl gorgosterol (1.74; -11.95) > 4.24-dimethyl-22-dehidrokolestanol (1.89; -11.90). The crucial residues of amino acids is 213-ASP, which play a significant role in hCHIT1 inhibitory activity. All components of the test compound have a log P value of more than five, which indicates that solubility and toxicity need to be considered. Evaluation of the pre-ADMET based on the value of plasma protein binding shows that the test compound can diffuse through the plasma membrane and interact according to pharmacological targets. In addition, the results of the toxicity test showed that 23-demethyl gorgosterol and 4.24-dimethyl-22-dehidrokolestanol compounds have potential as anti-asthma.

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Targeting Acidic Mammalian chitinase Is Effective in Animal Model of Asthma

Cited by 27 publications

References 30 publications

Synthesis of 3-(5-amino-1H-1,2,4-triazol-3-yl)propanamides and their tautomerism

Synthesis of 3-(5-amino-1H-1,2,4-triazol-3-yl)propanamides and their tautomerism

<p>Chitinases and Chitinase-Like Proteins in Obstructive Lung Diseases – Current Concepts and Potential Applications</p>

Virtual Screening Kandungan Senyawa Kipas Laut (Gorgonia mariae) sebagai Anti-Asma

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