Design, synthesis, and biological activity of potent and selective inhibitors of mast cell tryptase

Hopkins, Corey R.; Czekaj, Mark; Kaye, Steven S.; Gao, Zhongli; Pribish, James; Pauls, Henry W.; Liang, Guyan; Sides, Keith; Cramer, Dona; Cairns, Jennifer; Luo, Youfu; Lim, Heng Keang; Vaz, Roy J.; Rebello, Sam; Maignan, S.; Dupuy, Alain; Mathieu, Magali; Levell, Julian

doi:10.1016/j.bmcl.2005.04.002

Cited by 35 publications

(27 citation statements)

References 13 publications

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“…In 1998, the crystal structure of human bII-tryptase was solved for the first time, which revealed a tetramer structure where the monomer units were positioned at the corners of a flat rectangular frame. [11][12][13][14][15] The first class contains a reactive functional group that can form a covalent bond with catalytic serine in the active pocket. This special topology of the tetramer explains its resistance to biological inhibitors, including a1-antitrypsin, antithrombin III (ATIII), a2-macroglobulin (a2M), bovine aprotinin and plantderived inhibitors such as the soybean trypsin inhibitor (SBTI) and the lima bean trypsin inhibitor (LBTI).…”

Section: Introductionmentioning

confidence: 99%

Heparin makes differences: a molecular dynamics simulation study on the human βII-tryptase monomer

et al. 2015

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Human β-tryptase, an enzyme with trypsin-like activity in mast cells, is an important target for the treatment of inflammatory and allergy related diseases. Heparin has been inferred to play a vital role in the stabilization of the tryptase structure and the maintenance of its active form. Up to now, the structure-function relationship between heparin and the βII-tryptase monomer has not been studied with atomic resolution due to the lack of a complex structure of tryptase and heparin. To this end, the exact effect of heparin bonding to the βII-tryptase monomer structure has been investigated using molecular docking and molecular dynamics (MD) simulation. The MD simulation results combined with MM-GB/SA calculations showed that heparin stabilized the β-tryptase structure mainly through salt bridge interaction. The averaged noncovalent interaction (aNCI) method was employed for the visualization of nonbonding interactions. A crucial loop, which is located in the core region of βII-tryptase monomer structure, has been found. Arg188 and Asp189 from this loop act as a salt bridge intermediary between 4-mer heparin and 0GX. The observation of a salt bridge between Asp189 and P1 groups of 0GX confirms the supposed interaction between these two groups. These two residues have been proved to be responsible for the direction of the P1 group of 0GX. Our study revealed that how heparin affected the activity of the human βII-tryptase monomer (hBTM) through salt bridge interactions. The knowledge of heparin binding characteristics and the key residue contributions in this study may enlighten further the inhibitor design of this enzyme and may also improve our understanding of inflammatory and allergy related diseases.

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Section: Introductionmentioning

confidence: 99%

Heparin makes differences: a molecular dynamics simulation study on the human βII-tryptase monomer

et al. 2015

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“…From an achiral piperidine derivative, acting as a surrogate of the initial template, they developed a completely new class of βII-tryptase inhibitors termed 4-(3-aminomethylphenyl) piperidinyl-1-amides [61]. By using an indole scaffold as a hydrophobic substituent on a m-benzylaminepiperidine template, the same group developed a new series of potent and selective inhibitors of tryptase [62]. As of the end of August 2005, AVE8923, a β-tryptase inhibitor was in the preclinical stage for the treatment of asthma (http://en.sanofiaventis.com/rd/portfolio/p_rd_portfolio_medecine_interne.as p; access date: 17 Jan 2006).…”

Section: Targeting Tryptasementioning

confidence: 99%

Targeting Serine Proteases in Asthma

Guay¹,

Laviolette²,

Tremblay³

2006

CTMC

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Leukocytes and lung structural cells contribute to the pathophysiology of asthma through the production of numerous mediators including serine proteases. Such proteases include mast cell tryptase and chymase; neutrophil elastase, cathepsin G and myeloblastin (proteinase 3); bronchial epithelial cell-derived transmembrane protease, serine 11D (human airway trypsin-like protease); cytotoxic T lymphocyte- and natural killer cell-derived granzyme B; and, eosinophil serine protease 1 (testisin). Considerable effort to develop potent and selective inhibitors, mostly non-peptidic, especially targeting tryptase and chymase have been made in the last few years. This review presents promising inhibitors, currently in the research and development pipeline. Some endogenous inhibitors and other compounds purified from non-human species are also discussed.

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“…IICT-TA59 10 μg/ml 34 13 IICT-TA60 10 μg/ml 31 14 IICT-TA77 10 μg/ml 45 15 IICT-TA78 10 μg/ml 73 Rolipram 10 μg/ml 69…”

Section: Compound 11 Inhibits the Adhesion Of Neutrophils On Tnf-alphunclassified

“…The indole ring system is a very important component in many synthetic pharmaceuticals 12,13 and it is worth to note that the World Drug Index contains 74 indole derivatives as drug molecules. Furthermore, the indole 3-acetic acid and its derivatives are commonly used as building blocks for the synthesis of pharmaceutically important molecules 14 . Furthermore, the indole 3-acetic acid and its derivatives are commonly used as building blocks for the synthesis of pharmaceutically important molecules 14 .…”

Section: Introductionmentioning

confidence: 99%

A novel triazine-aryl-bis-indole derivative inhibits both phosphodiesterase IV and expression of cell adhesion molecules

et al. 2015

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Design, synthesis, and biological activity of potent and selective inhibitors of mast cell tryptase

Cited by 35 publications

References 13 publications

Heparin makes differences: a molecular dynamics simulation study on the human βII-tryptase monomer

Heparin makes differences: a molecular dynamics simulation study on the human βII-tryptase monomer

Targeting Serine Proteases in Asthma

A novel triazine-aryl-bis-indole derivative inhibits both phosphodiesterase IV and expression of cell adhesion molecules

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