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941.
Trapella C Guerrini R Piccagli L Calo' G Carra' G Spagnolo B Rubini S Fanton G Hebbes C McDonald J Lambert DG Regoli D Salvadori S 《Bioorganic & medicinal chemistry》2006,14(3):692-704
To date, J-113397 represents the most potent and selective non peptide NOP receptor antagonist widely used in pharmacological studies. However, the synthesis, purification, and enantiomer separation of this molecule, which contains two chiral centers, is rather difficult and low-yielding. Here, we synthesized and tested a series of simplified J-113397 analogues to investigate the importance of the stereochemistry and the influence of the substituents at position 3 of the piperidine nucleus and on the nitrogen atom of the benzimidazolidinone nucleus. The compound coded as Trap-101, an achiral analogue of J-113397, combines a pharmacological profile similar to that of the parent compound with a practical, high-yielding preparation. 相似文献
942.
Belvisi L Bernardi A Colombo M Manzoni L Potenza D Scolastico C Giannini G Marcellini M Riccioni T Castorina M LoGiudice P Pisano C 《Bioorganic & medicinal chemistry》2006,14(1):169-180
A small library of cyclic RGD pentapeptide mimics incorporating stereoisomeric 5,6- and 5,7-fused bicyclic lactams was synthesized. This library was found to contain high-affinity ligands for the alpha(v)beta3 integrin. The aim of this study was to investigate activity, selectivity, and structure of these ligands in order to identify new specific alpha(v)-integrin antagonists that could be evaluated as tumor angiogenesis inhibitors. In vitro screening, including receptor-binding assays to purified alpha(v)beta3, alpha(v)beta5, and alpha5beta1 integrins, and platelet aggregation assay, revealed ST1646 as a potent, highly selective alpha(v)beta3/alpha(v)beta5 integrin antagonist. Structure determination of the cyclic RGD pentapeptide mimics performed by a combination of NMR spectroscopy, and molecular mechanics and dynamics calculations showed a strong dependence of the RGD cyclopeptide conformation on lactam ring size and stereochemistry. ST1646 revealed the highest ability within the library to adopt the proper RGD orientation required for binding to the alpha(v)beta3 integrin, as deduced from the recently solved crystal structure of the extracellular segment of integrin alpha(v)beta3 in complex with a cyclic pentapeptide ligand. 相似文献
943.
Babini E Bertini I Capozzi F Chirivino E Luchinat C 《Structure (London, England : 1993)》2006,14(6):1029-1038
The structure and dynamics of human calmodulin-like skin protein (CLSP) have been characterized by NMR spectroscopy. The mobility of CLSP has been found to be different for the N-terminal and C-terminal domains. The isolated domains were also expressed and analyzed. The structure of the isolated C-terminal domain is presented. The N-terminal domain is characterized by four stable helices, which experience large fluctuations. This is shown to be due to mutations in the hydrophobic core. The overall N-terminal domain behavior is similar both in the full-length protein and in the isolated domain. By exploiting the capability of Tb3+ bound to CLSP to induce partial orientation of the molecule in a magnetic field, restricted motion of one domain with respect to the other was proved. By using NMR, ITC, and ESI-MS, the calcium and magnesium binding properties were investigated. Finally, CLSP is framed into the evolutionary scheme of the calmodulin-like family. 相似文献
944.
Efficient site-specific integration of large transgenes by an enhanced herpes simplex virus/adeno-associated virus hybrid amplicon vector
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We previously demonstrated that a herpes simplex virus type 1 (HSV-1)/adeno-associated virus (AAV) hybrid amplicon vector constructed by inserting the sequences of regulatory protein (rep) and inverted terminal repeats of AAV into an HSV amplicon vector resulted in the enhanced stability of transgene expression compared to the original HSV-1 amplicon vector. However, problems related to the expression of Rep compromised its therapeutic applications. We report here a new HSV/AAV hybrid amplicon vector system that not only solved problems associated with Rep expression but also markedly improved the stable transduction efficiency of this vector. This new HSV/AAV vector is designed in a way that little or no Rep would be expressed in packaging cells, but it can be expressed in transduced cells if Cre recombinase is provided. Furthermore, Rep expression will be automatically suppressed as a consequence of Rep-mediated integration. Our results showed that the new hybrid amplicon vector yielded titers comparable to those of standard amplicon vectors. When Cre-expressing 293 cells were transduced, a low level of Rep expression was detected, and stable transduction was achieved in approximately 22% of transduced cells; of those cells, approximately 70% transduction was achieved by Rep-mediated site-specific integration. In the majority of the stably transduced cells, Rep expression was no longer observed. Our results also proved that this vector system is capable of efficiently accommodating and site-specifically integrating large transgenes, such as the full-length dystrophin expression cassette. Thus, the new HSV/AAV vector demonstrated unique advantages in safe and effective delivery of long-lasting transgene expression into human cells. 相似文献
945.
Roth AL Marzola E Rizzi A Arduin M Trapella C Corti C Vergura R Martinelli P Salvadori S Regoli D Corsi M Cavanni P Caló G Guerrini R 《The Journal of biological chemistry》2006,281(30):20809-20816
Neuropeptide S (NPS) has been recently recognized as the endogenous ligand for the previous orphan G-protein-coupled receptor GPR154, now referred to as the NPS receptor (NPSR). The NPS-NPSR receptor system regulates important biological functions such as sleeping/wakening, locomotion, anxiety, and food intake. To collect information on the mechanisms of interaction between NPS and its receptor, a classical structure-activity relationship study was performed. Human (h) NPS derivatives obtained by Ala and d-scan and N- and C-terminal truncation were assessed for their ability to stimulate calcium release in HEK293 cells expressing the human recombinant NPSR. The results of this study indicate that (i) the effect of hNPS is mimicked by the fragment hNPS-(1-10); (ii) Phe(2), Arg(3), and Asn(4) are crucial for biological activity; (iii) the sequence Thr(8)-Gly(9)-Met(10) is important for receptor activation, although with non-stringent chemical requirements; and (iv) the sequence Val(6)-Gly(7) acts as a hinge region between the two above-mentioned domains. However, the stimulatory effect of hNPS given intracerebroventricularly on mouse locomotor activity was not fully mimicked by hNPS-(1-10), suggesting that the C-terminal region of the peptide maintains importance for in vivo activity. In conclusion, this study identified the amino acid residues of this peptide most important for receptor activation. 相似文献
946.
Prions are the unconventional infectious agents responsible for transmissible spongiform encephalopathies, which appear to be composed mainly or exclusively of the misfolded prion protein (PrPSc). Prion replication involves the conversion of the normal prion protein (PrPC) into the misfolded isoform, catalyzed by tiny quantities of PrPSc present in the infectious material. We have recently developed the protein misfolding cyclic amplification (PMCA) technology to sustain the autocatalytic replication of infectious prions in vitro. Here we show that PMCA enables the specific and reproducible amplification of exceptionally minute quantities of PrPSc. Indeed, after seven rounds of PMCA, we were able to generate large amounts of PrPSc starting from a 1x10(-12) dilution of scrapie hamster brain, which contains the equivalent of approximately 26 molecules of protein monomers. According to recent data, this quantity is similar to the minimum number of molecules present in a single particle of infectious PrPSc, indicating that PMCA may enable detection of as little as one oligomeric PrPSc infectious particle. Interestingly, the in vitro generated PrPSc was infectious when injected in wild-type hamsters, producing a disease identical to the one generated by inoculation of the brain infectious material. The unprecedented amplification efficiency of PMCA leads to a several billion-fold increase of sensitivity for PrPSc detection as compared with standard tests used to screen prion-infected cattle and at least 4000 times more sensitivity than the animal bioassay. Therefore, PMCA offers great promise for the development of highly sensitive, specific, and early diagnosis of transmissible spongiform encephalopathy and to further understand the molecular basis of prion propagation. 相似文献
947.
948.
Bacteriorhodopsin (bR) is presently a classical example of membrane protein crystallization. We are comparing the structure of bR with the homology model of octopus rhodopsin (octR), which is similar in topology to bR and as highly ordered in its native membranes as bR in purple membranes. Such comparison provides insights for optimization of present octR experimentation both for crystallization and for application in nanobiotechnology in a manner similar to bR, and possibly even superior in optical computation. 相似文献
949.
Sebastian Lugert Onur Basak Philip Knuckles Ute Haussler Klaus Fabel Magdalena Götz Carola A. Haas Gerd Kempermann Verdon Taylor Claudio Giachino 《Cell Stem Cell》2010,6(5):445-456
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950.
Claudio E. Torres Louis F. Rossi Jeremy Keffer Ke Li Chien-Chung Shen 《Swarm Intelligence》2010,4(3):221-244
Using the metaphor of swarm intelligence, ant-based routing protocols deploy control packets that behave like ants to discover
and optimize routes between pairs of nodes. These ant-based routing protocols provide an elegant, scalable solution to the
routing problem for both wired and mobile ad hoc networks. The routing problem is highly nonlinear because the control packets
alter the local routing tables as they are routed through the network. We mathematically map the local rules by which the
routing tables are altered to the dynamics of the entire networks. Using dynamical systems theory, we map local protocol rules
to full network performance, which helps us understand the impact of protocol parameters on network performance. In this paper,
we systematically derive and analyze global models for simple ant-based routing protocols using both pheromone deposition
and evaporation. In particular, we develop a stochastic model by modeling the probability density of ants over the network.
The model is validated by comparing equilibrium pheromone levels produced by the global analysis to results obtained from
simulation studies. We use both a Matlab simulation with ideal communications and a QualNet simulation with realistic communication
models. Using these analytic and computational methods, we map out a complete phase diagram of network behavior over a small
multipath network. We show the existence of both stable and unstable (inaccessible) routing solutions having varying properties
of efficiency and redundancy depending upon the routing parameters. Finally, we apply these techniques to a larger 50-node
network and show that the design principles acquired from studying the small model network extend to larger networks. 相似文献