Side chain effect in the modulation of αvβ3/α5β1 integrin activity via clickable isoxazoline-RGDmimetics: development of molecular delivery systems

View references (57) Construction of small molecule ligand (SML) based delivery systems has been performed starting from a polyfunctionalized isoxazoline scaffold, whose \u3b1v\u3b23 and \u3b15\u3b21 integrins\u2019 potency has been already established. The synthesis of this novel class of ligands was obtained by conjugation of linkers to the heterocyclic core via Huisgen-click reaction, with the aim to use them as \u201cshuttles\u201d for selective delivery of diagnostic agents to cancer cells, exploring the effects of the side chains in the interaction with the target. Compounds 17b and 24 showed excellent potency towards \u3b15\u3b21 integrin acting as selective antagonist and agonist respectively. Further investigations confirmed their effects on target receptor through the analysis of fibronectin-induced ERK1/2 phosphorylation. In addition, confocal microscopy analysis allowed us to follow the fate of EGFP conjugated \u3b15\u3b21 integrin and 17b FITC-conjugated (compound 31) inside the cells. Moreover, the stability in water solution at different values of pH and in bovine serum confirmed the possible exploitation of these peptidomimetic molecules for pharmaceutical application

Sustainability in peptide chemistry: current synthesis and purification technologies and future challenges.

Developing greener synthesis processes is an inescapable necessity to transform the industrial landscape, mainly in the pharmaceutical sector, into a long-term, sustainable reality. In this context, the renaissance of peptides as medical treatments, and the enforcement of more stringent sustainability requirements by regulatory agencies, pushed chemists toward the introduction of sustainable processes to prepare highly pure, active pharmaceutical ingredients (APIs). Innovative upstream (synthesis) and downstream (purification) methodologies have been developed during the last 5 years with the introduction and optimization of several technologies in solid-phase peptide synthesis (SPPS), liquid-phase peptide synthesis (LPPS), chemoenzymatic peptide synthesis (CEPS), and chromatographic procedures. These innovations are also moving toward the introduction of continuous processes that represent one of the most important targets for iterative processes. This overview discusses the most recent efforts in making peptide chemistry greener. The extensive studies that were carried out on green solvents, reaction conditions, auxiliary reagents and purification technologies in the peptide segment can be useful to other fields of organic synthesi

A novel immunoscintigraphy technique using metabolizable linker with angiotensin II treatment

Immunoscintigraphy is a tumour imaging technique that can have specificity, but high background radioactivity makes it difficult to obtain tumour imaging soon after the injection of radioconjugate. The aim of this study is to see whether clear tumour images can be obtained soon after injection of a radiolabelled reagent using a new linker with antibody fragments (Fab), in conditions of induced hypertension in mice. Fab fragments of a murine monoclonal antibody against human osteosarcoma were labelled with radioiodinated 3′-iodohippuryl N-ɛ-maleoyl-L-lysine (HML) and were injected intravenously to tumour-bearing mice. Angiotensin II was administered for 4 h before and for 1 h after the injection of radiolabelled Fab. Kidney uptake of 125I-labelled-HML-Fab was much lower than that of 125I-labelled-Fab radioiodinated by the chloramine-T method, and the radioactivity of tumour was increased approximately two-fold by angiotensin II treatment at 3 h after injection, indicating high tumour-to-normal tissue ratios. A clear tumour image was obtained with 131I-labelled-HML-Fab at 3 h post-injection. The use of HML as a radiolabelling reagent, combined with angiotensin II treatment, efficiently improved tumour targeting and enabled the imaging of tumours. These results suggest the feasibility of PET scan using antibody fragment labelled with 18F-fluorine substitute for radioiodine. © 1999 Cancer Research Campaig

Assessing ADHD symptoms in children and adults:Evaluating the role of objective measures

Background: Diagnostic guidelines recommend using a variety of methods to assess and diagnose ADHD. Applying subjective measures always incorporates risks such as informant biases or large differences between ratings obtained from diverse sources. Furthermore, it has been demonstrated that ratings and tests seem to assess somewhat different constructs. The use of objective measures might thus yield valuable information for diagnosing ADHD. This study aims at evaluating the role of objective measures when trying to distinguish between individuals with ADHD and controls. Our sample consisted of children (n = 60) and adults (n = 76) diagnosed with ADHD and matched controls who completed self- and observer ratings as well as objective tasks. Diagnosis was primarily based on clinical interviews. A popular pattern recognition approach, support vector machines, was used to predict the diagnosis. Results: We observed relatively high accuracy of 79% (adults) and 78% (children) applying solely objective measures. Predicting an ADHD diagnosis using both subjective and objective measures exceeded the accuracy of objective measures for both adults (89.5%) and children (86.7%), with the subjective variables proving to be the most relevant. Conclusions: We argue that objective measures are more robust against rater bias and errors inherent in subjective measures and may be more replicable. Considering the high accuracy of objective measures only, we found in our study, we think that they should be incorporated in diagnostic procedures for assessing ADHD

Reliabilität und Validität des Wender-Reimherr-Interviews (WRI). Ein Instrument zur Diagnostik der ADHS im Erwachsenenalter [freier Beitrag]

Grundlage der Diagnostik der ADHS (Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung) im Erwachsenenalter ist in der Regel die DSM-IV- oder ICD-10-Klassifikation. Für die Psychopathologie der Erwachsenen sind diese Systeme nur bedingt geeignet. Die Utah-Kriterien, die mit dem Wender-Reimher-Interview (WRI) erfasst werden können, beziehen sich explizit auf das Erwachsenenalter. Ziel der vorliegenden Studie war, die psychometrischen Charakteristiken sowie die Verteilung und Kombination der sieben Bereiche des WRI zu untersuchen und zudem einen Vergleich mit anderen Selbst- und Fremdbeurteilungsverfahren der ADHS-Diagnostik zu ziehen. Die Skalenhomogenität des WRI lag mit einem Cronbachs α von .88 hoch. Die Interrater-Reliabilität lag auf Itemebene zwischen .45 und .95. Hohe Korrelationen mit anderen Instrumenten bestätigten die konvergente Validität des Interviews. Das WRI erwies sich als ein reliables und valides Instrument, das über das dreidimensionale Modell der ADHS Unaufmerksamkeit, Hyperaktivität und Impulsivität hinausgeht und dabei die Symptomatik der erwachsenen ADHS-Patienten besser berücksichtigt

Combining human genetics of multiple sclerosis with oxidative stress phenotype for drug repositioning

In multiple sclerosis (MS), oxidative stress (OS) is implicated in the neurodegenerative processes that occur from the beginning of the disease. Unchecked OS initiates a vicious circle caused by its crosstalk with inflammation, leading to demyelination, axonal damage and neuronal loss. The failure of MS antioxidant therapies relying on the use of endogenous and natural compounds drives the application of novel approaches to assess target relevance to the disease prior to preclinical testing of new drug candidates. To identify drugs that can act as regulators of intracel-lular oxidative homeostasis, we applied an in silico approach that links genome-wide MS associa-tions and molecular quantitative trait loci (QTLs) to proteins of the OS pathway. We found 10 drugs with both central nervous system and oral bioavailability, targeting five out of the 21 top-scoring hits, including arginine methyltransferase (CARM1), which was first linked to MS. In particular, the direction of brain expression QTLs for CARM1 and protein kinase MAPK1 enabled us to select BIIB021 and PEITC drugs with the required target modulation. Our study highlights OS-related molecules regulated by functional MS variants that could be targeted by existing drugs as a supple-ment to the approved disease-modifying treatments