RESUMEN
Inwardly rectifying K+ (Kir) channels play a significant role in vertebrate and invertebrate biology by regulating the movement of K+ ions involved in membrane transport and excitability. Yet unlike other ion channels including their ancestral K+-selective homologs, there are very few venom toxins known to target and inhibit Kir channels with the potency and selectivity found for the Ca2+-activated and voltage-gated K+ channel families. It is unclear whether this is simply due to a lack of discovery, or instead a consequence of the evolutionary processes that drive the development of venom components towards their targets based on a collective efficacy to 1) elicit pain for defensive purposes, 2) promote paralysis for prey capture, or 3) facilitate delivery of venom components into the circulation. The past two decades of venom screening has yielded three venom peptides with inhibitory activity towards mammalian Kir channels, including the discovery of tertiapin, a high-affinity pore blocker from the venom of the European honey bee Apis mellifera. Venomics and structure-based computational approaches represent exciting new frontiers for venom peptide development, where re-engineering peptide 'scaffolds' such as tertiapin may aid in the quest to expand the palette of potent and selective Kir channel blockers for future research and potentially new therapeutics. This article is part of the Special Issue entitled 'Venom-derived Peptides as Pharmacological Tools.'
Asunto(s)
Péptidos , Bloqueadores de los Canales de Potasio , Canales de Potasio de Rectificación Interna/metabolismo , Ponzoñas , Animales , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Modelos Moleculares , Péptidos/química , Péptidos/historia , Péptidos/farmacología , Bloqueadores de los Canales de Potasio/química , Bloqueadores de los Canales de Potasio/historia , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio de Rectificación Interna/historia , Ponzoñas/química , Ponzoñas/historia , Ponzoñas/farmacologíaAsunto(s)
Amidas/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Atropina/farmacología , Sistema Nervioso Central/efectos de los fármacos , Difenoxilato/farmacología , Péptidos/farmacología , Peptidil-Dipeptidasa A/metabolismo , Inhibidores de la Enzima Convertidora de Angiotensina/química , Inhibidores de la Enzima Convertidora de Angiotensina/historia , Combinación de Medicamentos , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Péptidos/química , Péptidos/historia , Peptidil-Dipeptidasa A/historiaRESUMEN
The chemical synthesis of proteins has been the wish of chemists since the early 19th century. There were decisive methodological steps necessary to accomplish this aim. Cornerstones were the introduction of the Z-protecting group of Bergmann and Zervas, the development of Solid-phase Peptide Synthesis of Merrifield, and the establishment of Native Chemical Ligation by Kent. Chemical synthesis of proteins has now become generally applicable technique for the synthesis of proteins with tailor made properties which can be applied not only in vitro but also in vivo .Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.
Asunto(s)
Técnicas de Química Sintética/historia , Péptidos/síntesis química , Técnicas de Química Sintética/métodos , Historia del Siglo XX , Historia del Siglo XXI , Péptidos/química , Péptidos/historia , Proteínas/químicaRESUMEN
When the Davis Lab was first asked to contribute to this special edition of Peptides to celebrate the career and influence of Abba Kastin on peptide research, it felt like a daunting task. It is difficult to really understand and appreciate the influence that Abba has had, not only on a generation of peptide researchers, but also on the field of blood brain barrier (BBB) research, unless you lived it as we did. When we look back at our careers and those of our former students, one can truly see that several of Abba's papers played an influential role in the development of our personal research programs.
Asunto(s)
Barrera Hematoencefálica/metabolismo , Péptidos/metabolismo , Animales , Investigación Biomédica/historia , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Péptidos/historia , Transporte de Proteínas/fisiologíaRESUMEN
This following article is written for Prof. Abba Kastin's Festschrift, to add to the tribute to his important role in the advancement of the role of peptides in physiological, as well as pathophysiological processes. There have been many advances during the 35 years of his prominent role in the Peptide field, not only as editor of the journal Peptides, but also as a scientific investigator and editor of two volumes of the Handbook of Biological Active Peptides [146,147]. Similar to the advances with many different peptides, during this 35 year period, there have been much progress made in the understanding of the pharmacology, cell biology and the role of (bombesin) Bn receptors and their ligands in various disease states, since the original isolation of bombesin from skin of the European frog Bombina bombina in 1970 [76]. This paper will briefly review some of these advances over the time period of Prof. Kastin 35 years in the peptide field concentrating on the advances since 2007 when many of the results from earlier studies were summarized [128,129]. It is appropriate to do this because there have been 280 articles published in Peptides during this time on bombesin-related peptides and it accounts for almost 5% of all publications. Furthermore, 22 Bn publications we have been involved in have been published in either Peptides [14,39,55,58,81,92,93,119,152,216,225,226,231,280,302,309,355,361,362] or in Prof. Kastin's Handbook of Biological Active Peptides [137,138,331].
Asunto(s)
Péptidos/química , Péptidos/metabolismo , Receptores de Bombesina/agonistas , Animales , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Ligandos , Péptidos/historia , Publicaciones Periódicas como Asunto/historia , Receptores de Bombesina/historiaAsunto(s)
ADN de Forma Z/historia , Conformación de Ácido Nucleico , Biotecnología/historia , Colágeno/química , Colágeno/historia , Cristalografía por Rayos X , ADN de Forma Z/química , Historia del Siglo XX , Péptidos/química , Péptidos/historia , Polirribosomas/metabolismo , ARN/química , ARN/historia , Estados UnidosRESUMEN
Ruth Arnon and Michael Sela profoundly influenced the development of a model system to test new therapies in multiple sclerosis (MS). Their application of the animal model, known as experimental autoimmune encephalomyelitis (EAE), for the discovery of Copaxone, opened a new path for testing of drug candidates in MS. By measuring clinical, pathologic, and immunologic outcomes, the biological implications of new drugs could be elucidated. Using EAE they established the efficacy of Copaxone as a therapy for preventing and reducing paralysis and inflammation in the central nervous system without massive immune suppression. This had a huge impact on the field of drug discovery for MS. Much like the use of parabiosis to discover soluble factors associated with obesity, or the replica plating system to probe antibiotic resistance in bacteria, the pioneering research on Copaxone using the EAE model, paved the way for the discovery of other therapeutics in MS, including Natalizumab and Fingolimod. Future applications of this approach may well elucidate novel therapies for the neurodegenerative phase of multiple sclerosis associated with disease progression.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Encefalomielitis Autoinmune Experimental , Inmunosupresores , Esclerosis Múltiple , Péptidos , Glicoles de Propileno , Esfingosina/análogos & derivados , Animales , Anticuerpos Monoclonales Humanizados/historia , Anticuerpos Monoclonales Humanizados/uso terapéutico , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/historia , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/patología , Clorhidrato de Fingolimod , Acetato de Glatiramer , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Inmunosupresores/historia , Inmunosupresores/uso terapéutico , Esclerosis Múltiple/dietoterapia , Esclerosis Múltiple/historia , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Natalizumab , Péptidos/historia , Péptidos/uso terapéutico , Glicoles de Propileno/historia , Glicoles de Propileno/uso terapéutico , Esfingosina/historia , Esfingosina/uso terapéuticoAsunto(s)
Globinas/historia , Calor , Proteolisis , Reticulocitos/metabolismo , Adenosina Trifosfato/historia , Adenosina Trifosfato/metabolismo , Adenosina Trifosfato/farmacología , Animales , Sistema Libre de Células/metabolismo , Globinas/metabolismo , Historia del Siglo XX , Péptidos/historia , Péptidos/metabolismo , Estabilidad Proteica , Conejos , Reticulocitos/efectos de los fármacosRESUMEN
HLA-DR molecules are heterodimeric transmembrane glycoproteins that associate intracellularly with a polypeptide known as the invariant (I) chain. Shortly before expression of the HLA-DR αß dimer on the cell surface, however the I chain is removed from the intracellular αßI complex by a mechanism thought to involve proteolysis . In this report, we show that treatment of purified αßI with the cysteine proteinase cathepsin B results in the specific proteolysis of the HLA-DR-associated I chain in vitro. As a consequence of this, the I chain is removed and free αß dimers are released from αßI. Although αßI fails to bind an immunogenic peptide, the released αß dimers acquire the ability to bind the peptide after proteolysis of the I chain. These results suggest that the I chain inhibits immunogenic peptide binding to αßI early during intracellular transport and demonstrate that proteolysis is likely to be the in vivo mechanism of I chain removal.
Asunto(s)
Antígenos de Diferenciación de Linfocitos B/historia , Antígenos HLA-DR/historia , Antígenos de Histocompatibilidad Clase II/historia , Líquido Intracelular/inmunología , Péptidos/historia , Antígenos de Diferenciación de Linfocitos B/química , Línea Celular Transformada , Endocitosis/inmunología , Antígenos HLA-DR/química , Antígenos de Histocompatibilidad Clase II/química , Historia del Siglo XX , Humanos , Hidrólisis , Líquido Intracelular/química , Péptidos/antagonistas & inhibidores , Péptidos/química , Unión Proteica/inmunología , Multimerización de Proteína/inmunología , Transporte de Proteínas/inmunologíaAsunto(s)
Presentación de Antígeno/inmunología , Reactividad Cruzada/inmunología , Antígenos H-2/historia , Péptidos/historia , Animales , Antígenos H-2/inmunología , Historia del Siglo XX , Historia del Siglo XXI , Ratones , Ratones Endogámicos BALB C/inmunología , Ratones Endogámicos C57BL/inmunología , Antígenos de Histocompatibilidad Menor/historia , Antígenos de Histocompatibilidad Menor/inmunología , Péptidos/inmunología , Linfocitos T Citotóxicos/inmunologíaRESUMEN
Although age-related macular degeneration is the most prevalent macular disease in the world, numerous discoveries regarding the molecular bases of vision have been made through genetic association studies of rare inherited maculopathies. In this issue of the JCI, Yang et al. present a functional genetics study that identifies a role for prominin 1 (PROM1), best known as a stem cell and/or progenitor cell marker, in the biogenesis of retinal photoreceptor disk arrays (see the related article beginning on page 2908). This study supports an established model in which disk morphogenesis occurs through membrane evagination and extends other recent studies assigning PROM1 important functions outside of the stem cell niche.