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1.  Microwave-Assisted Solid-Phase Synthesis of side-chain to side-chain lactam-bridge cyclic peptides 
Side-chain to side-chain lactam-bridged cyclic peptides have been utilized as therapeutic agents and biochemical tools. Previous synthetic methods of these peptides need special reaction conditions, form side products and take longer reaction times. Herein, an efficient microwaveassisted synthesis of side-chain to side-chain lactam-bridge cyclic peptides SHU9119 and MTII is reported. The synthesis time and efforts are significantly reduced in the present method, without side product formation. The analytical and pharmacological data of the synthesized cyclic peptides are in accordance with the commercially obtained compounds. This new method could be used to synthesize other side-chain to side-chain lactam-bridge peptides and amenable to automation and extensive SAR compound derivatization.
Graphical Abstract
doi:10.1016/j.bmcl.2015.10.095
PMCID: PMC4654418  PMID: 26555357
Cyclic peptides; Microwave assisted synthesis; Lactam-bridge cyclic peptides; SHU9119; MTII
2.  A Fragment of the Escherichia coli ClpB Heat-Shock Protein is a Micromolar Melanocortin 1 Receptor Agonist 
The melanocortin system consists of five receptor subtypes (MC1-5R), endogenous agonists derived from the proopiomelanocortin gene transcript, and the antagonists agouti and agouti-related protein. The Escherichia coli heat shock protein ClpB has previously been described as an antigen mimetic to the endogenous melanocortin agonist α-MSH. Herein, we investigated if a fragment of the ClpB protein could directly signal through the melanocortin receptors. We synthesized a complementary fragment of the ClpB protein that partially aligned with α-MSH. Pharmacological assessment of this fragment resulted in no antagonist activity at the MC3R or the MC4R and no agonist activity at the MC4R. Partial receptor activation was observed for the MC3R and MC5R at 100 μM concentrations. This fragment was shown to be a full micromolar MC1R agonist and may serve as a template for future research into selective MC1R ligands.
Graphical Abstract
doi:10.1016/j.bmcl.2015.09.046
PMCID: PMC4628882  PMID: 26433448
Melanocortin Receptors; ClpB Heat Shock Protein; NDP-MSH; α-MSH; AlphaScreen® cAMP Assay
3.  Decoy Plasminogen Receptor Containing a Selective Kunitz-Inhibitory Domain 
Biochemistry  2014;53(3):505-517.
Kunitz domain 1 (KD1) of tissue factor pathway inhibitor-2 in which P2′ residue Leu17 (bovine pancreatic trypsin inhibitor numbering) is mutated to Arg selectively inhibits the active site of plasmin with ∼5-fold improved affinity. Thrombin cleavage (24 h extended incubation at a 1:50 enzyme-to-substrate ratio) of the KD1 mutant (Leu17Arg) yielded a smaller molecule containing the intact Kunitz domain with no detectable change in the active-site inhibitory function. The N-terminal sequencing and MALDI-TOF/ESI data revealed that the starting molecule has a C-terminal valine (KD1L17R-VT), whereas the smaller molecule has a C-terminal lysine (KD1L17R-KT). Because KD1L17R-KT has C-terminal lysine, we examined whether it could serve as a decoy receptor for plasminogen/plasmin. Such a molecule might inhibit plasminogen activation as well as the active site of generated plasmin. In surface plasmon resonance experiments, tissue plasminogen activator (tPA) and Glu-plasminogen bound to KD1L17R-KT (Kd ∼ 0.2 to 0.3 μM) but not to KD1L17R-VT. Furthermore, KD1L17R-KT inhibited tPA-induced plasma clot fibrinolysis more efficiently than KD1L17R-VT. Additionally, compared to ε-aminocaproic acid KD1L17R-KT was more effective in reducing blood loss in a mouse liver-laceration injury model, where the fibrinolytic system is activated. In further experiments, the micro(μ)-plasmin–KD1L17R-KT complex inhibited urokinase-induced plasminogen activation on phorbol-12-myristate-13-acetate-stimulated U937 monocyte-like cells, whereas the μ-plasmin–KD1L17R-VT complex failed to inhibit this process. In conclusion, KD1L17R-KT inhibits the active site of plasmin as well as acts as a decoy receptor for the kringle domain(s) of plasminogen/plasmin; hence, it limits both plasmin generation and activity. With its dual function, KD1L17R-KT could serve as a preferred agent for controlling plasminogen activation in pathological processes.
doi:10.1021/bi401584b
PMCID: PMC3985851  PMID: 24383758
4.  Effect of ethanolic fruit extract of Cucumis trigonus Roxb. on antioxidants and lipid peroxidation in urolithiasis induced wistar albino rats 
Ancient Science of Life  2011;31(1):10-16.
Urolithiasis was induced using ethylene glycol in wistar albino rats, the formation of calcium stones in the kidney results with the damage of antioxidant system. Ethanolic extract of Cucumis trigonus Roxb fruit of family Curcurbitaceae was used to treat urolithiasis. On this course, the extract also repairs the changes that happened in the enzymatic, non enzymatic antioxidants and lipid peroxidation in liver and kidney of urolithiasis induced rats. The results obtained from the analysis were compared at 5% level of significance using one way ANOVA. The results show that the ethanolic fruit extract has repaired the levels of antioxidants and malondialdehyde to their normal levels.
PMCID: PMC3377036  PMID: 22736884
Cucumis trigonus; Antioxidants; malondialdehyde; ethylene glycol
5.  Biopotency of Acalypha indica Linn on Membrane Bound ATPases and Marker Enzymes urolithic Rats 
Ancient Science of Life  2011;31(1):3-9.
The ethanolic extract of Acalypha indica was tested for its biopotency on membrane bound enzymes and marker enzymes in urolithiasis in male wistar albino rats. Calcium oxalate urolithiasis was induced by 0.75% ethylene glycol in drinking water for 30 days. There was a significant decrease in membrane bound enzymes such as Ca2+ ATPase, Mg2+ ATPase, Na+K+ ATPase and marker enzymes Aspartate Transaminase (AST), Alanine Transaminase (ALT), Acid phosphatase (ACP) and Alkaline Phosphatase (ALP) in liver and kidney. The AST, ALT, ACP and ALP were increased in serum and urine of rats. Therapeutic treatment with plant extract (200mg/kg b.wt.dose-1 day-1 oral-1) has significantly ameliorated to near normalcy in the curative group. These results of the present study concluded that A. indica can play an important role in the prevention of disorders associated with kidney stone formation.
PMCID: PMC3377040  PMID: 22736883
Marker enzymes; membrane bound enzymes; Urolithiasis; ethylene glycol; Acalypha indica

Results 1-5 (5)