scholarly journals Design, Synthesis and Characterization of Cyclic NU172 Analogues: A Biophysical and Biological Insight

2020 ◽  
Vol 21 (11) ◽  
pp. 3860 ◽  
Author(s):  
Claudia Riccardi ◽  
Albert Meyer ◽  
Jean-Jacques Vasseur ◽  
Domenico Cavasso ◽  
Irene Russo Krauss ◽  
...  
Keyword(s):  
Anticoagulant Activity ◽  
Design Synthesis ◽  
Conformational Constraints ◽  
Biological Insight ◽  
Human Thrombin ◽  
Nuclease Resistance ◽  
Biophysical Techniques ◽  
Ligation Method

NU172—a 26-mer oligonucleotide able to bind exosite I of human thrombin and inhibit its activity—was the first aptamer to reach Phase II clinical studies as an anticoagulant in heart disease treatments. With the aim of favoring its functional duplex-quadruplex conformation and thus improving its enzymatic stability, as well as its thrombin inhibitory activity, herein a focused set of cyclic NU172 analogues—obtained by connecting its 5′- and 3′-extremities with flexible linkers—was synthesized. Two different chemical approaches were exploited in the cyclization procedure, one based on the oxime ligation method and the other on Cu(I)-assisted azide-alkyne cycloaddition (CuAAC), affording NU172 analogues including circularizing linkers with different length and chemical nature. The resulting cyclic NU172 derivatives were characterized using several biophysical techniques (ultraviolet (UV) and circular dichroism (CD) spectroscopies, gel electrophoresis) and then investigated for their serum resistance and anticoagulant activity in vitro. All the cyclic NU172 analogues showed higher thermal stability and nuclease resistance compared to unmodified NU172. These favorable properties were, however, associated with reduced—even though still significant—anticoagulant activity, suggesting that the conformational constraints introduced upon cyclization were somehow detrimental for protein recognition. These results provide useful information for the design of improved analogues of NU172 and related duplex-quadruplex structures.

Assays for Phospholipid-Dependent Formation of Thrombin and Xa: A Potential Method for Quantifying Lupus Anticoagulant Activity

1991 ◽  
Vol 66 (04) ◽  
pp. 453-458 ◽  
Author(s):  
John T Brandt
Keyword(s):  
Specific Activity ◽  
Anticoagulant Activity ◽  
Factor Xa ◽  
Clinical Importance ◽  
Potential Method ◽  
Quantitative Expression ◽  
Increased Risk ◽  
Apparent Association

SummaryLupus anticoagulants (LAs) are antibodies which interfere with phospholipid-dependent procoagulant reactions. Their clinical importance is due to their apparent association with an increased risk of thrombo-embolic disease. To date there have been few assays for quantifying the specific activity of these antibodies in vitro and this has hampered attempts to purify and characterize these antibodies. Methods for determining phospholipid-dependent generation of thrombin and factor Xa are described. Isolated IgG fractions from 7 of 9 patients with LAs were found to reproducibly inhibit enzyme generation in these assay systems, permitting quantitative expression of inhibitor activity. Different patterns of inhibitory activity, based on the relative inhibition of thrombin and factor Xa generation, were found, further substantiating the known heterogeneity of these antibodies. These systems may prove helpful in further purification and characterization of LAs.

scholarly journals Design, synthesis, and in vitro characterization of novel hybrid peptidomimetic inhibitors of STAT3 protein

2011 ◽  
Vol 19 (5) ◽  
pp. 1823-1838 ◽  
Author(s):  
Vijay M. Shahani ◽  
Peibin Yue ◽  
Steven Fletcher ◽  
Sumaiya Sharmeen ◽  
Mahadeo A. Sukhai ◽  
...  
Keyword(s):  
Design Synthesis ◽  
In Vitro Characterization ◽  
Peptidomimetic Inhibitors

scholarly journals Design, Synthesis and Characterization of a New Series of Fluorescent Metabotropic Glutamate Receptor Type 5 Negative Allosteric Modulators

Molecules ◽  
2020 ◽  
Vol 25 (7) ◽  
pp. 1532
Author(s):  
Víctor Fernández-Dueñas ◽  
Mingcheng Qian ◽  
Josep Argerich ◽  
Carolina Amaral ◽  
Martijn D.P. Risseeuw ◽  
...  
Keyword(s):  
Binding Sites ◽  
Metabotropic Glutamate Receptor ◽  
Allosteric Modulators ◽  
Design Synthesis ◽  
Metabotropic Glutamate ◽  
Animal Disease Models ◽  
Fluorescent Ligands ◽  
The Brain

In recent years, new drug discovery approaches based on novel pharmacological concepts have emerged. Allosteric modulators, for example, target receptors at sites other than the orthosteric binding sites and can modulate agonist-mediated activation. Interestingly, allosteric regulation may allow a fine-tuned regulation of unbalanced neurotransmitter’ systems, thus providing safe and effective treatments for a number of central nervous system diseases. The metabotropic glutamate type 5 receptor (mGlu5R) has been shown to possess a druggable allosteric binding domain. Accordingly, novel allosteric ligands are being explored in order to finely regulate glutamate neurotransmission, especially in the brain. However, before testing the activity of these new ligands in the clinic or even in animal disease models, it is common to characterize their ability to bind mGlu5Rs in vitro. Here, we have developed a new series of fluorescent ligands that, when used in a new NanoBRET-based binding assay, will facilitate screening for novel mGlu5R allosteric modulators.

scholarly journals Design, Synthesis and Characterization of Some Novel benzamide derivatives and it's Pharmacological Screening

2020 ◽  
pp. 68-74 ◽  
Author(s):  
Akshay R. Yadav ◽  
Shrinivas K. Mohite
Keyword(s):  
Chemical Structure ◽  
Design Synthesis ◽  
Different Types ◽  
Anti Inflammatory ◽  
Benzoyl Isothiocyanate ◽  
Pharmacological Screening ◽  
Benzamide Derivatives

The new series of substituted N-(phenylcarbamothioyl)benzamide derivatives (2a-2f) was designed, development and synthesized by using conventional and microwave method. In present work 6 different N-(phenylcarbamothioyl)benzamide were synthesized. Substituted benzoyl chloride is converted into benzoyl isothiocyanate by esterification. Benzoyl isothiocyanate is converted into Substituted (phenylcarbamothioyl)benzamide by treating with different types of substituted aniline. Confirmation of the chemical structure of the synthesized was substantiated by TLC, IR, 1H NMR, MS spectroscopy.Novel synthesized compounds screened for their in vivo and in-vitro anti-inflammatory studies and compound 2f shows promising anti-inflammatory activity.

Design, synthesis and characterization of hydroxyapatite-chitosan nanocomposite radiolabelled with 153Sm as radiopharmaceutical for use in radiosynovectomy

2019 ◽  
Vol 108 (1) ◽  
pp. 57-65
Author(s):  
Sima Attar Nosrati ◽  
Robabeh Alizadeh ◽  
Seyed Javad Ahmadi ◽  
Mostafa Erfani
Keyword(s):  
Chemical Structure ◽  
Therapeutic Agent ◽  
Radiochemical Purity ◽  
Saline Solution ◽  
Wild Type ◽  
Design Synthesis ◽  
Physiochemical Properties

Abstract The aim of the present study was to introduction of hydroxyapatite/chitosan nanocomposite as a new radiosynovectomy agent with excellent properties. In this work, the nanocomposite was prepared through a reliable method and characterized using different techniques to elucidate its chemical structure and physiochemical properties. The prepared nanocomposite was successfully radiolabeled with 153Sm under optimal conditions and with high radiolabelling yield (99 %). The radiochemical purity of the prepared radiopharmaceutical was found to be >99 % as determined by ITLC technique. In vitro stability studies in saline solution and in human serum showed that the radiolabeled nanocomposite retained its stability for at least 6 days. The biodistribution and imaging studies in wild-type rats revealed high retention of the agent into the synovial joints of the knee even at 96 h post-injection, thereby indicating excellent in vivo stability of 153Sm labeled hydroxyapatite-chitosan nanocomposite. Therefore, the prepared radiopharmaceutical would be a potential therapeutic agent for use in radiosynovectomy procedure.

Sign in / Sign up

Export Citation Format

Share Document