Discovery of biphenyl pyrazole scaffold for neurodegenerative diseases: A novel class of acetylcholinesterase-centered multitargeted ligands

Multitargeted ligands have demonstrated remarkable efficiency as potential therapeutics for neurodegenerative diseases as they target multiple pathways involved in the progression of these diseases. Herein, we report first-in-class dual inhibitor of acetylcholinesterase (AChE) and tau aggregation as a novel class of multitargeted ligands for neurodegenerative diseases. The reported biphenyl pyrazole scaffold binds monomeric tau with submicromolar affinity and impedes the formation of tau oligomers at early stages. Additionally, the lead compound inhibited AChE activity with an IC₅₀ value of 0.35 ± 0.02 μM. Remarkably, the neuroprotective effect of this lead in induced cytotoxicity model of SH-SY5Y neuroblastoma cells is superior to single-targeted AChE and tau-aggregation inhibitors. This scaffold would enable development of new generation of multitargeted ligands for neurodegenerative diseases that function through dual targeting of AChE and monomeric tau.     

Molecular probes for the human adenosine receptors

Adenosine receptors, G protein–coupled receptors (GPCRs) that are activated by the endogenous ligand adenosine, have been considered potential therapeutic targets in several disorders. To date however, only very few adenosine receptor modulators have made it to the market. Increased understanding of these receptors is required to improve the success rate of adenosine receptor drug discovery. To improve our understanding of receptor structure and function, over the past decades, a diverse array of molecular probes has been developed and applied. These probes, including radioactive or fluorescent moieties, have proven invaluable in GPCR research in general. Specifically for adenosine receptors, the development and application of covalent or reversible probes, whether radiolabeled or fluorescent, have been instrumental in the discovery of new chemical entities, the characterization and interrogation of adenosine receptor subtypes, and the study of adenosine receptor behavior in physiological and pathophysiological conditions. This review summarizes these applications, and also serves as an invitation to walk another mile to further improve probe characteristics and develop additional tags that allow the investigation of adenosine receptors and other GPCRs in even finer detail.

     

A novel peptide specifically targeting ovarian cancer identified by in vivo phage display

Discovery of peptide ligands that can target human ovarian cancer and deliver chemotherapeutics offers new opportunity for cancer therapy. The advent of phage‐displayed peptide library facilitated the screening of such peptides. In vivo screening that set in a microanatomic and functional context was applied in our study, and a novel peptide WSGPGVWGASVK targeting ovarian cancer was isolated. The phage clone PC3‐1 displaying peptide WSGPGVWGASVK can gain effective access to accumulate in the tumor sites after intravenous injection while reducing its accumulation in normal organs. Positive immunostaining of PC3‐1 was located in both sites of tumor cells and tumor blood vessels, which resulted in a diffuse binding pattern through the tumor. In vitro study results confirmed the capability of peptide WSGPGVWGASVK binding to and being internalized by both tumor cells and angiogenic endothelial cells. Flow cytometry analysis revealed that the peptide bound to SKOV3 cells with Kd value of 5.43 ± 0.4 μM. Taken together, it suggested that peptide WSGPGVWGASVK is a lead candidate for delivering therapeutics to penetrate into tumors. Copyright © 2013 European Peptide Society and John Wiley & Sons, Ltd.     

Myocardial bridging: what have we learned in the past and will new diagnostic modalities provide new insights?

The clinical significance of myocardial bridging has been a subject of discussion and controversy since the introduction of coronary arteriography (CAG) in the early 1960s. More recently computed tomography coronary angiography (CTCA) has made it possible to visualise the overlying muscular bands and appears to have a higher sensitivity for detecting myocardial bridging than CAG. Combining CTCA with invasive techniques such as CAG should make it possible to improve our understanding of the pathophysiology of myocardial bridging and to provide answers to hitherto unresolved questions. This paper critically reviews the outcomes of previous studies and defines remaining questions that should be answered to optimise the management of the presumably fast growing number of patients in whom a diagnosis of myocardial bridging has been made.     

Eph receptors and their ligands: Promising molecular biomarkers and therapeutic targets in prostate cancer

Although at present, there is a high incidence of prostate cancer, particularly in the Western world, mortality from this disease is declining and occurs primarily only from clinically significant late stage tumors with a poor prognosis. A major current focus of this field is the identification of new biomarkers which can detect earlier, and more effectively, clinically significant tumors from those deemed “low risk”, as well as predict the prognostic course of a particular cancer. This strategy can in turn offer novel avenues for targeted therapies. The large family of Receptor Tyrosine Kinases, the Ephs, and their binding partners, the ephrins, has been implicated in many cancers of epithelial origin through stimulation of oncogenic transformation, tumor angiogenesis, and promotion of increased cell survival, invasion and migration. They also show promise as both biomarkers of diagnostic and prognostic value and as targeted therapies in cancer. This review will briefly discuss the complex roles and biological mechanisms of action of these receptors and ligands and, with regard to prostate cancer, highlight their potential as biomarkers for both diagnosis and prognosis, their application as imaging agents, and current approaches to assessing them as therapeutic targets. This review demonstrates the need for future studies into those particular family members that will prove helpful in understanding the biology and potential as targets for treatment of prostate cancer.     

Models of the pharmacophoric pattern and affinity trend of methyl 2-(aminomethyl)-1-phenylcyclopropane-1-carboxylate derivatives as σ1 ligands

Sigma-1 (σ₁) affinities of methyl 2-(aminomethyl)-1-phenylcyclopropane-1-carboxylate (MAPCC) derivatives were modelled by the genetic algorithm with linear assignment of hypermolecular alignment of datasets (GALAHAD) and the comparative molecular field analysis (CoMFA)/comparative molecular similarity indices analysis (CoMSIA) methods. GALAHAD was used for deriving the 3D pharmacophore pattern that encompasses the most potent σ₁ ligands within this series. Five MAPCC derivatives with a high σ₁ affinity were used for deriving this model. The obtained model included a nitrogen atom, the hydrophobes and the hydrogen bond acceptor features; it was able to identify other potent σ₁ ligands. On the other hand, CoMFA and CoMSIA methods were used for deriving quantitative structure–activity relationship (QSAR) models. All QSAR models were trained with 17 compounds, after which they were evaluated for predictive ability with additional five compounds. The best QSAR model was obtained by using CoMSIA, including steric, electrostatic and hydrophobic fields, and had a good predictive quality according to both internal and external validation criteria. In general, the models described herein provide meaningful information relevant for the rational design of new σ₁ ligands.     

Kinetics of adsorption of extended ligands on DNA at small fillings

In the present work, the adsorption kinetics of extended ligands on DNA duplexes at small fillings when molecules of DNA duplexes are on the underlayer within diffusion layer has been investigated. Both diffusion of ligands in solution (diffusion stage) and adsorption of ligands (kinetic stage) are taken into consideration at adsorption of ligands on DNA duplexes. Nonlinear system of differential equations describing adsorption of ligands where not only diffusion stage but also kinetic stage is taken into account, is obtained, moreover the equations allow localizing duplexes in arbitrary place within diffusion layer. Numeric solution of the equations makes possible to investigate the filling kinetics of DNA duplexes by ligands depending on parameters controlling adsorption process. It has been shown that depending on relation between adsorption parameters different kinetic regimes of adsorption – kinetic, complex, and diffusion regimes may be realized.     

‘We all eat the same bread’: the roots and limits of cosmopolitan bridging ties developed by Romanians in London

This paper investigates the social ties forged by Romanians in London with migrants of different origins in work and non-work contexts to offer a more nuanced view of ‘bridging’ social ties and related discussions of ‘everyday’ cosmopolitanism. Contrary to the overemphasis on ethnic ties seen as a form of bonding in migration research, the paper shows how Romanians bridge informally with many other migrants based on shared ‘non-native’ status. Alongside non-ethnically marked commonalities, ethnicity emerges as an important ingredient of cosmopolitan socialization, yet without necessarily signalling coexisting ethnic identities, as commonly assumed. Romanians' experiences further show that despite providing significant social and cultural capital, bridging ties with migrants, rather than natives, rarely accrue effective resources for social mobility. The findings suggest the need to disaggregate and qualify current understandings of ‘bridging’ social ties usually depicted in positive terms and uniformly as cross-ethnic relationships, or only linked with the ‘mainstream’ population.     

Discovery of highly potent and selective D4 ligands by interactive SAR study

A series of thienylmethylphenylpiperazins was synthesized and tested for affinity towards the five subtypes of dopaminergic receptors. Compound 5f showed more than 1000 folds selectivity to D4 receptors; analogue 5e showed the highest affinity to D4 receptors with K_i 3.9 nM. An interactive SAR approach was adopted and lead to compound 14a with K_i (D4) as low as 0.03 nM. Molecular docking studies showed a potential, first to report arene cation interaction between the D4 unique residue Arg-186 and the ligands’ arene moiety, explaining the importance of having a strong negative electrostatic potential at this area of the compound structure.     

Design,synthesis, and biological characterization of novel PEG-linked dimeric modulators for CXCR4

CXCR4 dimerization has been widely demonstrated both biologically and structurally. This paper mainly focused on the development of structure-based dimeric ligands that target CXCL12–CXCR4 interaction and signaling. This study presents the design and synthesis of a series of [PEG]_n linked dimeric ligands of CXCR4 based on the knowledge of the homodimeric crystal structure of CXCR4 and our well established platform of chemistry and bioassays for CXCR4. These new ligands include [PEG]_n linked homodimeric or heterodimeric peptides consisting of either two DV3-derived moieties (where DV3 is an all-d-amino acid analog of N-terminal modules of 1–10 (V3) residues of vMIP-II) or hybrids of DV3 moieties and CXCL12_1–8. Among a total of 24 peptide ligands, four antagonists and three agonists showed good CXCR4 binding affinity, with IC₅₀ values of <50 nM and <800 nM, respectively. Chemotaxis and calcium mobilization assays with SUP-T1 cells further identified two promising lead modulators of CXCR4: ligand 4, a [PEG₃]₂ linked homodimeric DV3, was an effective CXCR4 antagonist (IC₅₀ = 22 nM); and ligand 21, a [PEG₃]₂ linked heterodimeric DV3–CXCL12_1–8, was an effective CXCR4 agonist (IC₅₀ = 407 nM). These dimeric CXCR4 modulators represent new molecular probes and therapeutics that effectively modulate CXCL12–CXCR4 interaction and function.