Opioid activity profiles of oversimplified peptides lacking in the protonable N-terminus

Recently, we described cyclopeptide opioid agonists containing the D-Trp-Phe sequence. To expand the scope of this atypical pharmacophore, we tested the activity profiles of the linear peptides Ac-Xaa-Phe-Yaa (Xaa = L/D-Trp, D-His/Lys/Arg; Yaa = H, GlyNH2). Ac-D-Trp-PheNH2 appeared to be the minimal binding sequence, while Ac-D-Trp-Phe-GlyNH 2 emerged as the first noncationizable short peptide (partial) agonist with high \u3bc-opioid receptor affinity and selectivity. Conformational analysis suggested that 5 adopts in solution a \u3b2-turn conformation. \ua9 2012 American Chemical Society

Spectroscopic fingerprints of DNA/RNA pyrimidine nucleobases in third-order nonlinear electronic spectra

Accurate ab initio modeling of spectroscopic signals in nonlinear electronic spectra, such as bidimensional (2D) spectra, requires the computation of the electronic transitions induced by the incoming pump/probe pulses, resulting in a challenging calculation of many electronic excited states. A protocol is thus required to evaluate the variations of spectral properties, like transition energies and dipole moments, with the computational level, and to estimate the sensitivity of the spectra to these variations. Such a protocol is presented here within the framework of complete and restricted active space self-consistent field (CASSCF/RASSCF) theory and its second-order perturbation theory extensions (CASPT2/RASPT2). The electronic excited-state manifolds of pyrimidine nucleobases (thymine, uracil, and cytosine) are carefully characterized in vacuo employing high-level RAS(0,0|10,8|2,12)//SS-RASPT2 calculations. The results provide a reference data set that can be used for optimizing computational efforts and costs, as required for studying computationally more demanding multichromophoric systems (e.g., di- and oligonucleotides). The spectroscopic signatures of the 2D electronic spectrum of a perfectly stacked uracil–cytosine dimer model are characterized, and experimental setups are proposed that can resolve non-covalent interchromophoric interactions in canonical pyrimidine nucleobase-stacked dimers

Expedient synthesis of pseudo-Pro-containing peptides: Towards constrained peptidomimetics and foldamers

The reaction of sulfonyl peptides containing l- or d-configured Ser or Thr with bis(succinimidyl) carbonate in the presence of a catalytic amount of a base affords, in solution or in the solid phase, the corresponding peptides with one or two, consecutive or alternate oxazolidin-2-ones (Oxd). The Oxd ring can be regarded to as a pseudo-Pro with an exclusively trans conformation of the preceding peptide bond; homochiral Oxd-containing peptides adopt extended conformations, while the presence of a d-configured Oxd favours folded conformations. © The Royal Society of Chemistry 2012

In-peptide synthesis of di-oxazolidinone and dehydroamino acid-oxazolidinone motifs as \u3b2-turn inducers

Small and easy-to-do mimetics of \u3b2-turns are of great interest to interfere with protein-protein recognition events mediated by \u3b2-turn recognition motifs. We propose a straightforward procedure for constraining the conformation of tetrapeptides lacking a pre-formed scaffold. According to the stereochemistry array, N-Ts tetrapeptides including Thr or PhSer (phenylserine) at the positions 2 or 3 gave rise in a single step to the sequences Oxd 2-Oxd3 or \u394Abu2-Oxd3 (Oxd, oxazolidin-2-one; \u394Abu, 2,3-dehydro-2-aminobutyric). These pseudo-Pro residues displayed highly constrained, and \u3c7 dihedral angles, and induced clear \u3b2-turns or inverse turns of type I or II, as determined by extensive spectroscopic and computational analyses. \ua9 The Royal Society of Chemistry 2013

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

The Stress and its Influence on the Health of the Nursing Professionals: The Case of Preceptors of a Clinical School

A pesquisa tem como objeto as condições geradoras de estresse e sua influência na saúde dos enfermeiros preceptores de uma clínica escola de enfermagem de uma Instituição de Ensino Superior (IES). Objetivos: Descrever as condições geradoras de estresse no ambiente de trabalho dos enfermeiros preceptores de uma clínica escola e analisar a influência sobre a saúde desses profissionais decorrentes das condições geradoras de estresse. Metodología: Estudo exploratório, com abordagem qualitativa, tendo como sujeitos sete enfermeiros (7), que corresponde a 78% do total de profissionais entrevistados.Utilizou-se roteiro de entrevista semiéstruturada. Ressultados principais: Os discursos foram analisados buscando a apreensão das condições geradoras de estresse e como esses fatores influenciam na saúde dos enfermeiros preceptores. Desse modo, a análise dos discursos possibilitou a formulação de duas categorias: I - Reconhecendo as fontes geradoras de estresse, sendo que esta apresenta três subcategorías temáticas: Assédio moral, Atraso de Salário e Sobrecarga de trabalho. II- A influência na saúde decorrente dos fatores geradores de estresse. Conclusão principal: As condições de trabalho constituem um fator predisponente para gerar estresse, sendo que estas condições englobam tudo que influencia o próprio trabalho: o ambiente, os meios, a tarefa, a jornada, a organização do trabalho, a alimentação, o salário e as relações interpessoais. O estudo aponta que o estresse pode ser um fator desencadeante de doenças. Neste contexto, observa-se a necessidade de elaborar estratégias eficientes, para tomada de medidas preventivas de forma que se possa previnir os agravos à saúde desses trabalhadores.Abstract: This research aims to study the conditions that lead to stress and their influence on the health of nurses in a clinical preceptors nursing school of a private Higher Education Institution (HEI) in Rio de Janeiro, Brazil. Having objectives as: Describing the conditions that generate stress in the work environment of nurses and tutors and analyze the influence on the health of these professionals. Methodology: A qualitative exploratory study. For data collection we used a scripted semi structured interview. The subjects were 07 nurses preceptors who work at a clinic in al HEI school, corresponding to 78% of these professionals in the studied environment. The results showed that the stress response is an individual process and that for some workers, the perception and aggravations are higher. This research adds to other studies and confirms that stress can be a factor triggering various diseases. . The discourses analyzed showed two categories, the first being: Recognizing the sources of stress that included three subcategories: bullying, salary and workload and the second category: the influence on health due to the factors causing stress. It is important to highlight that within this context, it is noted the need for tracing strategies through the collaborative initiative involving the entire academic institution, requiring not only the knowledge of the factors causing stress, as well as the adoption of preventive measures of this problem, increasing the recognition and appreciation of the professional and seeking ways to improve the quality of life of its workers

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

Steps towards sustainable solid phase peptide synthesis: use and recovery ofN-octyl pyrrolidone

The investigation of new green biogenic pyrrolidinones as alternative solvents toN,N-dimethylformamide (DMF) for solid phase peptide synthesis (SPPS) led to the identification ofN-octyl pyrrolidone (NOP) as the best candidate. NOP showed good performances in terms of swelling, coupling efficiency and low isomerization generating peptides with very high purity. A mixture of NOP with 20% dimethyl carbonate (DMC) allowed a decrease in solvent viscosity, making the mixture suitable for the automated solid-phase protocol. Aib-enkephalin and linear octreotide were successfully used to test the methodologies. It is worth noting that NOP, DMC and the piperidine used in the deprotection step could be easily recovered by direct distillation from the process waste mixture. The process mass intensity (PMI), being reduced by 63-66%, achieved an outstanding value representing a clear step forward in achieving green SPPS

O Estresse e sua Influência na Saúde dos Profissionais de Enfermagem: O Caso dos Preceptores de uma Clínica Escola

A pesquisa tem como objeto as condições geradoras de estresse e sua influência na saúde dos enfermeiros preceptores de uma clínica escola de enfermagem de uma Instituição de Ensino Superior (IES). Objetivos:  Descrever as condições geradoras de estresse no ambiente de trabalho dos enfermeiros preceptores de uma clínica escola e analisar a influência sobre a saúde desses profissionais decorrentes das condições geradoras de estresse. Metodología: Estudo exploratório, com abordagem qualitativa, tendo como sujeitos sete enfermeiros (7),  que corresponde a 78% do total de profissionais entrevistados.Utilizou-se roteiro de entrevista semiéstruturada.  Ressultados principais: Os discursos foram analisados buscando a apreensão das condições geradoras de estresse e como esses fatores influenciam na saúde dos enfermeiros preceptores. Desse modo, a análise dos discursos possibilitou a formulação de duas categorias: I - Reconhecendo as fontes geradoras de estresse, sendo que esta apresenta três subcategorias temáticas: Assédio moral, Atraso de Salário e Sobrecarga de trabalho. II- A influência na saúde decorrente dos fatores geradores de estresse. Conclusão principal: As condições de trabalho constituem um fator predisponente para gerar estresse, sendo que estas condições englobam tudo que influencia o próprio trabalho: o ambiente, os meios, a tarefa, a jornada, a organização do trabalho, a alimentação, o salário e as relações interpessoais. O estudo aponta que o estresse pode ser um fator desencadeante de doenças. Neste contexto, observa-se a necessidade de elaborar estratégias eficientes, para tomada de medidas preventivas de forma que se possa previnir os agravos à saúde desses trabalhadores

Strategies to inhibit tumour associated integrin receptors: rationale for dual and multi-antagonists

YesThe integrins are a family of 24 heterodimeric transmembrane cell surface receptors. Involvement in cell attachment to the extracellular matrix, motility, and proliferation identifies integrins as therapeutic targets in cancer and associated conditions; thrombosis, angiogenesis and osteoporosis. The most reported strategy for drug development is synthesis of an agent that is highly selective for a single integrin receptor. However, the ability of cancer cells to change their integrin repertoire in response to drug treatment renders this approach vulnerable to the development of resistance and paradoxical promotion of tumor growth. Here, we review progress towards development of antagonists targeting two or more members of the RGD-binding integrins, notably αvβ3, αvβ5, αvβ6, αvβ8, α5β1, and αIIbβ3, as anticancer therapeutics