Amino Acids and Peptides. LIII. Synthesis and Biological Activities of Some Pseudo-Peptide Analogs of PKSI-527, a Plasma Kallikrein Selective Inhibitor. The Importance of the Peptide Backbone.

Fukumizu, Atsuko; Tsuda, Yoko; Wanaka, Keiko; Tada, Mayako; Okamoto, Shosuke; Hijikata-Okunomiya, Akiko; Okada, Yoshio

doi:10.1248/cpb.47.1141

Cited by 6 publications

(8 citation statements)

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“…Additional controls showed that DS-induced hydrolysis was inhibited by the kallikrein inhibitor trans-4-aminomethylcy-clohexanecarbonyl-L-phenylalanyl–4-aminopheny l acetic acid (PKSI-527). 29 We did not detect significant hydrolysis in FXII-deficient plasma treated with DS (data not shown). Together, these results suggest that PdSP15a is able to attenuate contact phase activation by DS in plasma.…”

Section: Resultsmentioning

confidence: 73%

Novel Family of Insect Salivary Inhibitors Blocks Contact Pathway Activation by Binding to Polyphosphate, Heparin, and Dextran Sulfate

Alvarenga

Oliveira

et al. 2013

ATVB

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Objective Polyphosphate and heparin are anionic polymers released by activated mast cells and platelets that are known to stimulate the contact pathway of coagulation. These polymers promote both the autoactivation of factor XII and the assembly of complexes containing factor XI, prekallikrein, and high-molecular-weight kininogen. We are searching for salivary proteins from blood-feeding insects that counteract the effect of procoagulant and proinflammatory factors in the host, including elements of the contact pathway. Approach and Results Here, we evaluate the ability of the sand fly salivary proteins, PdSP15a and PdSP15b, to inhibit the contact pathway by disrupting binding of its components to anionic polymers. We attempt to demonstrate binding of the proteins to polyphosphate, heparin, and dextran sulfate. We also evaluate the effect of this binding on contact pathway reactions. We also set out to determine the x-ray crystal structure of PdSP15b and examine the determinants of relevant molecular interactions. Both proteins bind polyphosphate, heparin, and dextran sulfate with high affinity. Through this mechanism they inhibit the autoactivation of factor XII and factor XI, the reciprocal activation of factor XII and prekallikrein, the activation of factor XI by thrombin and factor XIIa, the cleavage of high-molecular-weight kininogen in plasma, and plasma extravasation induced by polyphosphate. The crystal structure of PdSP15b contains an amphipathic helix studded with basic side chains that forms the likely interaction surface. Conclusions The results of these studies indicate that the binding of anionic polymers by salivary proteins is used by blood feeders as an antihemostatic/anti-inflammatory mechanism.

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Section: Resultsmentioning

confidence: 73%

Novel Family of Insect Salivary Inhibitors Blocks Contact Pathway Activation by Binding to Polyphosphate, Heparin, and Dextran Sulfate

Alvarenga

Oliveira

et al. 2013

ATVB

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“…The reaction was carried out in PBS, pH 7.4, using citrated human plasma 1 : 20, 4 μ M of the Abz-peptidyl-EDDnp substrate and 20 nM of the contact system activator DXS (500 kDa). As internal controls, the plasma was pretreated with the synthetic PKa inhibitor (PKSI-527—5 μ M) [38]. Assays with recombinant ISP-2 (kindly supplied by A. P. C. A. Lima) were performed at final concentrations of 142, 177, 240, and 355 nM; the neutrophil elastase (NE) inhibitor MeOSuc-AAPV-CMK (Calbiochem) was tested at 10, 20, and 30 μ M. PKSI or recombinant ISP2 and MeOSuc-AAPV-CMK were preincubated with human plasma for 15 min, at 37°C, prior to the addition of DXS and the substrate.…”

Section: Methodsmentioning

confidence: 99%

Ecotin-Like ISP ofL. majorPromastigotes Fine-Tunes Macrophage Phagocytosis by Limiting the Pericellular Release of Bradykinin from Surface-Bound Kininogens: A Survival Strategy Based on the Silencing of Proinflammatory G-Protein Coupled Kinin B₂and B₁Receptors

Svensjö

Almeida

Vellasco

et al. 2014

Mediators of Inflammation

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Inhibitors of serine peptidases (ISPs) expressed by Leishmania major enhance intracellular parasitism in macrophages by targeting neutrophil elastase (NE), a serine protease that couples phagocytosis to the prooxidative TLR4/PKR pathway. Here we investigated the functional interplay between ISP-expressing L. major and the kallikrein-kinin system (KKS). Enzymatic assays showed that NE inhibitor or recombinant ISP-2 inhibited KKS activation in human plasma activated by dextran sulfate. Intravital microscopy in the hamster cheek pouch showed that topically applied L. major promastigotes (WT and Δisp2/3 mutants) potently induced plasma leakage through the activation of bradykinin B2 receptors (B2R). Next, using mAbs against kininogen domains, we showed that these BK-precursor proteins are sequestered by L. major promastigotes, being expressed at higher % in the Δisp2/3 mutant population. Strikingly, analysis of the role of kinin pathway in the phagocytic uptake of L. major revealed that antagonists of B2R or B1R reversed the upregulated uptake of Δisp2/3 mutants without inhibiting macrophage internalization of WT L. major. Collectively, our results suggest that L. major ISP-2 fine-tunes macrophage phagocytosis by inhibiting the pericellular release of proinflammatory kinins from surface bound kininogens. Ongoing studies should clarify whether L. major ISP-2 subverts TLR4/PKR-dependent prooxidative responses of macrophages by preventing activation of G-protein coupled B2R/B1R.

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“…Regarding antibacterial activities, it can be clearly observed that compounds 6a, 6b, 7d, 8b, 10 and 11 were the highly active compounds. 13 C NMR spectra were run in DMSO-d6 on Jeol 500 MHz ( 1 H) and 125 MHz ( 13 C) instruments. Mass spectra were run on a MAT Finnigan SSQ 7000 spectrometer, using the Electron Impact technique (EI).…”

Section: Chemistrymentioning

confidence: 99%

“…Also, some pyridinecarboxamide analogs were designed and used as PARP-1 inhibitors [10], mycobacterium tuberculosis agents [11] and as CB2 cannabinoid receptor partial agonists [12]. On the other hand, In addition, heterocyclic compounds containing an amino acid or a peptide structural moiety showed biological [13] and antibacterial activities [14]. A branched-chain amino acid (BCAA: Leu, Ile, and Val) mixture has been used for treatment of hypoalbuminemia in patients with decompensated liver cirrhosis in Japan [15].…”

Section: Introductionmentioning

confidence: 99%

Antimicrobial activities of some synthesized macrocyclic pentaazapyridine and dipeptide pyridine derivatives

Flefel¹,

Alsafi²,

Alahmadi³

et al. 2018

biomedicalresearch

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A series of tetracarboxamide Schiff base and macrocyclic pentaazapyridines has been prepared from 3,5-bis(N-(1-hydrazinyl-1-oxo-3-phenylpropan-2-yl))pyridine carboxamide 4 as starting material, which was synthesized from 3,5-dinicotinic acid 1. Treatment of 4 with 1,4-diaminobutane, 1,6-diaminohexane or cycloalkanone derivatives gave the corresponding macrocyclic tetracarboxamides 5a and 5b, and cycloalkyl Schiff bases 6a-6c, respectively. Treatment of 4 with acetophenone or acetylpyridine derivatives gave the corresponding Schiff bases 7a-7e and 8a-8c, respectively. Carboxylic acid hydrazide 4 was treated with acid anhydrides in glacial acetic acid to afford the corresponding diimide tetracarboxamides 9-11, respectively. The structures of newly synthesized compounds are established by physical and spectral data evidences. Some of the synthesized compounds were screened as antimicrobial agents.

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Amino Acids and Peptides. LIII. Synthesis and Biological Activities of Some Pseudo-Peptide Analogs of PKSI-527, a Plasma Kallikrein Selective Inhibitor. The Importance of the Peptide Backbone.

Cited by 6 publications

References 1 publication

Novel Family of Insect Salivary Inhibitors Blocks Contact Pathway Activation by Binding to Polyphosphate, Heparin, and Dextran Sulfate

Novel Family of Insect Salivary Inhibitors Blocks Contact Pathway Activation by Binding to Polyphosphate, Heparin, and Dextran Sulfate

Ecotin-Like ISP ofL. majorPromastigotes Fine-Tunes Macrophage Phagocytosis by Limiting the Pericellular Release of Bradykinin from Surface-Bound Kininogens: A Survival Strategy Based on the Silencing of Proinflammatory G-Protein Coupled Kinin B₂and B₁Receptors

Antimicrobial activities of some synthesized macrocyclic pentaazapyridine and dipeptide pyridine derivatives

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Amino Acids and Peptides. LIII. Synthesis and Biological Activities of Some Pseudo-Peptide Analogs of PKSI-527, a Plasma Kallikrein Selective Inhibitor. The Importance of the Peptide Backbone.

Cited by 6 publications

References 1 publication

Novel Family of Insect Salivary Inhibitors Blocks Contact Pathway Activation by Binding to Polyphosphate, Heparin, and Dextran Sulfate

Novel Family of Insect Salivary Inhibitors Blocks Contact Pathway Activation by Binding to Polyphosphate, Heparin, and Dextran Sulfate

Ecotin-Like ISP ofL. majorPromastigotes Fine-Tunes Macrophage Phagocytosis by Limiting the Pericellular Release of Bradykinin from Surface-Bound Kininogens: A Survival Strategy Based on the Silencing of Proinflammatory G-Protein Coupled Kinin B2and B1Receptors

Antimicrobial activities of some synthesized macrocyclic pentaazapyridine and dipeptide pyridine derivatives

Contact Info

Product

Resources

About

Ecotin-Like ISP ofL. majorPromastigotes Fine-Tunes Macrophage Phagocytosis by Limiting the Pericellular Release of Bradykinin from Surface-Bound Kininogens: A Survival Strategy Based on the Silencing of Proinflammatory G-Protein Coupled Kinin B₂and B₁Receptors