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1.
J Med Chem ; 63(5): 2358-2371, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-31589041

RESUMO

G-protein-coupled receptors like the human Y1 receptor (hY1R) are promising targets in cancer therapy due to their high overexpression on cancer cells and their ability to internalize together with the bound ligand. This mechanism was exploited to shuttle boron atoms into cancer cells for the application of boron neutron capture therapy (BNCT), a noninvasive approach to eliminate cancer cells. A maximized number of carboranes was introduced to the hY1R-preferring ligand [F7,P34]-NPY by solid phase peptide synthesis. Branched conjugates loaded with up to 80 boron atoms per peptide molecule exhibited a maintained receptor activation profile, and the selective uptake into hY1R-expressing cells was demonstrated by internalization studies. In order to ensure appropriate solubility in aqueous solution, we proved the need for eight hydroxyl groups per carborane. Thus, we suggest the utilization of bis-deoxygalactosyl-carborane building blocks in solid phase peptide synthesis to produce selective boron delivery agents for BNCT.

2.
J Org Chem ; 85(3): 1446-1457, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-31813224

RESUMO

Boron neutron capture therapy (BNCT) allows the selective elimination of malignant tumor cells without affecting healthy tissue. Although this binary radiotherapy approach has been known for decades, BNCT failed to reach the daily clinics to date. One of the reasons is the lack of selective boron delivery agents. Using boron loaded peptide conjugates, which address G protein-coupled receptors overexpressed on tumor cells allow the intracellular accumulation of boron. The gastrin-releasing peptide receptor (GRPR) is a well-known target in cancer diagnosis and can potentially be used for BNCT. Here, we present the successful introduction of multiple bis-deoxygalactosyl-carborane building blocks to the GRPR-selective ligand [d-Phe6, ß-Ala11, Ala13, Nle14]Bn(6-14) (sBB2L) generating peptide conjugates with up to 80 boron atoms per molecule. Receptor activation was retained, metabolic stability was increased, and uptake into PC3 cells was proven without showing any intrinsic cytotoxicity. Furthermore, undesired uptake into liver cells was suppressed by using l-deoxygalactosyl modified carborane building blocks. Due to its high boron loading and excellent GRPR selectivity, this conjugate can be considered as a promising boron delivery agent for BNCT.

3.
ChemMedChem ; 13(17): 1797-1805, 2018 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-29979487

RESUMO

Adrenomedullin (ADM) is a peptide hormone of the calcitonin gene-related peptide (CGRP) family. It is involved in the regulation of cardiovascular processes such as angiogenesis, vasodilation, and the reduction of oxidative stress. ADM mediates its effects by activation of the ADM-1 and -2 receptors (AM1 R/AM2 R), but also activates the CGRP receptor (CGRPR) with reduced potency. It binds to the extracellular domains of the receptors with its C-terminal binding motif (residues 41-52). The activation motif, consisting of a disulfide-bonded ring structure (residues 16-21) and an adjacent helix (residues 22-30), binds to the transmembrane region and stabilizes the receptor conformation in the active state. While it was shown that the binding motif of ADM guides AM1 R selectivity, there is little information on the activation motif itself. Here, we demonstrate that Thr22 of ADM contributes to the selectivity. By using solid-phase peptide synthesis and cAMP-based signal transduction, we studied the effects of analogues in the activation motif of ADM on AM1 R and CGRPR activity. Our results indicate that Thr22 terminates the α-helix and orients the ring segment by hydrogen bonding. Using olefin stapling, we showed that the α-helical arrangement of the ring segment leads to decreased AM1 R activity, but does not affect CGRPR activation. These results demonstrate that the conformation of the ring segment of ADM has a strong impact on the selectivity within the receptor system.


Assuntos
Adrenomedulina/farmacologia , Proteína Semelhante a Receptor de Calcitonina/antagonistas & inibidores , Cardiotônicos/farmacologia , Treonina/química , Adrenomedulina/química , Proteína Semelhante a Receptor de Calcitonina/metabolismo , Cardiotônicos/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
4.
Dtsch Arztebl Int ; 114(47): 795-796, 2017 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-29229042
5.
J Med Chem ; 59(12): 5695-705, 2016 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-27166982

RESUMO

The 52 amino acid peptide hormone adrenomedullin (ADM) plays a major role in the development and regulation of the cardiovascular and lymphatic system and has therefore gained significant interest for clinical applications. Because adrenomedullin exhibits low metabolic stability, enhancement of the plasma half-life is essential for peptide-based drug design. Fluorescently labeled ADM analogues synthesized by Fmoc/t-Bu solid phase peptide synthesis were used to analyze their enzymatic degradation and specific fragmentation pattern in human blood plasma. The determination of important cleavage sites allowed the development of selectively modified peptides in a rational approach. By combination of palmitoylation, lactam-bridging, and Nα-methylation, ADM analogues protected from enzymatic cleavage in human blood were developed and revealed an explicitly elongated half-life of 5 days in comparison to the wild-type in vitro. This triple-modification did not alter the selectivity of the analogues at the AM1 receptor, highlighting their potential for therapeutic applications.


Assuntos
Adrenomedulina/metabolismo , Adrenomedulina/sangue , Adrenomedulina/química , Adrenomedulina/farmacologia , Células Cultivadas , Estabilidade de Medicamentos , Células HEK293 , Meia-Vida , Humanos , Estrutura Molecular , Receptores de Adrenomedulina/agonistas , Receptores de Adrenomedulina/metabolismo , Relação Estrutura-Atividade
8.
Ger Med Sci ; 13: Doc05, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26161049

RESUMO

This opinion deals critically with the so-called complementary and alternative medical (CAM) therapy on the basis of current data. From the authors' perspective, CAM prescriptions and most notably the extensive current endeavours to the "integration" of CAM into conventional patient care is problematic in several respects. Thus, several CAM measures are used, although no specific effects of medicines can be proved in clinical studies. It is extensively explained that the methods used in this regard are those of evidence-based medicine, which is one of the indispensable pillars of science-oriented medicine. This standard of proof of efficacy is fundamentally independent of the requirement of being able to explain efficacy of a therapy in a manner compatible with the insights of the natural sciences, which is also essential for medical progress. Numerous CAM treatments can however never conceivably satisfy this requirement; rather they are justified with pre-scientific or unscientific paradigms. The high attractiveness of CAM measures evidenced in patients and many doctors is based on a combination of positive expectations and experiences, among other things, which are at times unjustified, at times thoroughly justified, from a science-oriented view, but which are non-specific (context effects). With a view to the latter phenomenon, the authors consider the conscious use of CAM as unrevealed therapeutic placebos to be problematic. In addition, they advocate that academic medicine should again systematically endeavour to pay more attention to medical empathy and use context effects in the service of patients to the utmost. The subsequent opinion discusses the following after an introduction to medical history: the definition of CAM; the efficacy of most common CAM procedures; CAM utilisation and costs in Germany; characteristics of science-oriented medicine; awareness of placebo research; pro and contra arguments about the use of CAM, not least of all in terms of aspects related to medical ethics.


Assuntos
Terapias Complementares , Medicina Baseada em Evidências , Efeito Placebo , Antroposofia , Pesquisa Biomédica , Terapias Complementares/economia , Terapias Complementares/ética , Alemanha , Homeopatia , Humanos , Fitoterapia
9.
J Pept Sci ; 21(12): 905-12, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26767744

RESUMO

The human adrenomedullin (ADM) is a 52 amino acid peptide hormone belonging to the calcitonin family of peptides, which plays a major role in the development and regulation of cardiovascular and lymphatic systems. For potential use in clinical applications, we aimed to investigate the fate of the peptide ligand after binding and activation of the adrenomedullin receptor (AM1), a heterodimer consisting of the calcitonin receptor-like receptor (CLR), a G protein-coupled receptor, associated with the receptor activity-modifying protein 2 (RAMP2). Full length and N-terminally shortened ADM peptides were synthesized using Fmoc/tBu solid phase peptide synthesis and site-specifically labeled with the fluorophore carboxytetramethylrhodamine (Tam) either by amide bond formation or copper(I)-catalyzed azide alkyne cycloaddition. For the first time, Tam-labeled ligands allowed the observation of co-internalization of the whole ligand-receptor complex in living cells co-transfected with fluorescent fusion proteins of CLR and RAMP2. Application of a fluorescent probe to track lysosomal compartments revealed that ADM together with the CLR/RAMP2-complex is routed to the degradative pathway. Moreover, we found that the N-terminus of ADM is not a crucial component of the peptide sequence in terms of AM1 internalization behavior.


Assuntos
Adrenomedulina/química , Peptídeos/síntese química , Peptídeos/metabolismo , Receptores de Adrenomedulina/metabolismo , Adrenomedulina/metabolismo , Proteína Semelhante a Receptor de Calcitonina/química , Proteína Semelhante a Receptor de Calcitonina/genética , Proteína Semelhante a Receptor de Calcitonina/metabolismo , Corantes Fluorescentes/química , Células HEK293 , Humanos , Lisossomos/ultraestrutura , Peptídeos/química , Transporte Proteico , Proteína 2 Modificadora da Atividade de Receptores/química , Proteína 2 Modificadora da Atividade de Receptores/genética , Proteína 2 Modificadora da Atividade de Receptores/metabolismo , Receptores de Adrenomedulina/genética , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Rodaminas/química
18.
Z Evid Fortbild Qual Gesundhwes ; 103(5): 249-52, 2009.
Artigo em Alemão | MEDLINE | ID: mdl-19645337

RESUMO

Effectiveness does not always mean benefit but there is no benefit without effectiveness. Benefit does not always involve necessity but there is no necessity without benefit. In spite of this simple relationship these three important terms of the social security regulations are not well-defined. The array of the terms "effectiveness", "benefit" and "necessity" exhibits a decreasing accuracy of definition, a diminishing popularity in the context of scientific discourse, a rising importance for cost compensation, an increase of context dependencies and growing judgement dependence.


Assuntos
Julgamento , Previdência Social/economia , Tomada de Decisões , Assistência à Saúde/normas , Alemanha , Humanos , Relações Médico-Paciente , Previdência Social/legislação & jurisprudência , Fatores Socioeconômicos
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