Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P61278 (somatostatin)
22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Targeted fluorescent dyes are of substantial value for the intraoperative delineation of primary tumors and metastatic lesions. For this purpose long-wavelength red light (lambda=550-650 nm) offers advantages because of good tissue penetration and direct visibility. Since somatostatin receptors (SSTR) are overexpressed in a number of tumors, a series of potentially tumor-selective peptide-dye conjugates were synthesized by solid-phase peptide synthesis (SPPS). The octapeptides octreotate, Tyr(3)-octreotate and Tyr(3)-octreotide were employed and exhibited high affinity for somatostatin receptors (SSTR). The fluorescent dyes rhodamine 101, sulforhodamine B acid chloride, sulforhodamine 101 or rhodamine B isothiocyanate were conjugated either directly or via spacers, for example the peptidase-labile pentapeptide sequence Ala-Leu-Ala-Leu-Ala. The conjugates were completely assembled on the solid support: Fmoc-SPPS, cyclization via a disulfide linkage, N-terminal attachment of a spacer, and linkage to the fluorescent dye. An in vitro competition assay revealed that the conjugates bind to SSTRs with IC(50) values between 0.7 and 89 nM. The conjugates were generally stable to hydrolysis at pH 7-8 in buffer or serum. However, the rhodamine 101 conjugates revealed a loss of absorption at alkaline pH due to conversion to a neutral spirolactam form, as characterized by NMR.
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PMID:Fluorescent somatostatin receptor probes for the intraoperative detection of tumor tissue with long-wavelength visible light. 1205 43

For many tissue engineering applications biomimetic or bioactive polymers would allow for a more precise control of cell behavior in growing tissues than has so far been possible. For this application recently developed amine reactive diblock copolymers (N-succinimidyl tartrate monoamine poly(ethylene glycol)-block-poly(D,L-lactic acid) [ST-NH-PEGxPLAy]) were investigated concerning their reactivity in binding model substances. Their ability to covalently immobilize proteins on their surfaces was examined using polymer films with amine reactive surfaces. Furthermore, thiol reactive polymers were obtained by attaching N-succinimidyl 3-maleinimido propionate, a thiol reactive linker to monoamine poly(ethylene glycol)-block-poly(D,L-lactic acid) [H2N-PEGxPLAy]. This allowed the immobilization of proteins carrying free thiol groups. The amine and thiol reactive polymers were characterized by 1H-NMR spectroscopy and gel permeation chromatography (GPC). Investigation of glass transitions temperatures using modulated differential scanning calorimetry proved suitability for the fabrication of polymeric scaffolds for tissue engineering applications. The functionality of the polymers was demonstrated by investigating their ability to bind model amines, like the fluorescent dye EDANS. Moreover, insulin and somatostatin were covalently attached to the active linker groups via amine and thiol groups. The polymers will permit covalently attaching different bioactive molecules, such as growth and differentiation factors, with fast and gentle procedures securing their biological activity.
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PMID:The use of poly(ethylene glycol)-block-poly(lactic acid) derived copolymers for the rapid creation of biomimetic surfaces. 1292 57

The three-dimensional NMR structures of eight cyclic octapeptide analogues of somatostatin (SRIF) are described. These analogues, with the basic sequence H-c[Cys(3)-Phe(6)-Xxx(7)-Yyy(8)-Lys(9)-Thr(10)-Zzz(11)-Cys(14)]-OH (the numbering refers to the position in native SRIF), with Xxx(7) being Phe/Ala/Tyr, Yyy(8) being Trp/DTrp/D-threo-beta-Me2Nal/L-threo-beta-Me2Nal, and Zzz(11) being Phe/Ala, exhibit potent and highly selective binding to human SRIF type 4 (sst(4)) receptors. The conformations reveal that the backbones of these analogues do not have the usual type-II' beta-turn reported in the literature for sst(2)-subtype-selective analogues. Instead, the structures contain a unique arrangement of side chains of Yyy(8), Lys(9), and Phe(6) or Phe(11). The conformational preferences and results from biological analyses of these analogues (parts 1-3 of this series, Rivier et al., Erchegyi et al., and Erchegyi et al., J. Med. Chem. 2003, preceding papers in this issue) allow a detailed study of the structure-activity relationship of SRIF. The proposed consensus structural motif at the binding pocket for the sst(4)-selective analogues requires a unique set of distances between an indole/2-naphthyl ring, a lysine side chain, and another aromatic ring. This motif is necessary and sufficient to explain the binding affinities of all of the analogues studied and is distinct from the existing model suggested for sst(2)/sst(5) selectivity.
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PMID:Novel sst(4)-selective somatostatin (SRIF) agonists. 4. Three-dimensional consensus structure by NMR. 1466 15

Somatostatin receptor type 1 was modelled based on the atomic structure of bovine rhodopsin. Possible ways of binding interaction between somatostatin receptor type 1 and TT-232, a cycloheptapeptide analogue of somatostatin with broad therapeutic potential, were analysed by molecular docking. The twelve TT-232 conformations, obtained by NMR measurements in H(2)O-D(2)O mixture, were similar, disclosing a consensus backbone conformation. Several residues interacting with TT-232, such as Val133, Asp137 (helix 3), Arg197 (helix 4), Phe287, Gln291, Asn294 (helix 6), Ser305, and Tyr313 (helix 7), were found. In accordance, in vitro binding experiments indicated high-affinity binding of TT-232 to (125)I labelled somatostatin sites in brain membranes. The single binding crevice obtained by docking may allow the design and discovery of new peptidomimetics of TT-232 in the future.
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PMID:Binding crevice for TT-232 in a homology model of type 1 somatostatin receptor. 1504 92

177Lu of specific activity approximately 100-110 TBq/g and radionuclidic purity of approximately 100% was obtained by irradiation of enriched Lu2O3 (60.6% 176Lu) target for 7 days at a thermal neutron flux of 3 x 10(13)n/cm2/sec. The 177Lu labeling of a macrocyclic bifunctional chelating agent viz. 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) has been extensively studied. Lanreotide, [beta-naphthyl-Ala-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2] a disulfide-linked cyclic octapeptide and a somatostatin analog, reported to bind with a wide variety of tumors expressing somatostatin receptors, was conjugated with DOTA. The peptide-BFCA conjugate was characterized with the help of high-resolution two-dimensional proton NMR spectroscopy. The 177Lu labeling of the DOTA-lanreotide conjugate has been standardized to give a radiolabeling yield of 85%. The tracer showed specific binding with A-431 human epidermoid carcinoma and IMR-32 human brain neuroblastoma cells.
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PMID:177Lu-DOTA-lanreotide: a novel tracer as a targeted agent for tumor therapy. 1524 66

Previously reported results suggest that the analogue of the somatostatin des-AA1,2,5[D-Trp8,IAmp9]-somatostatin (CH-275) peptide bearing chelating agents able to coordinate radioactive metals could be used for scintigraphic imaging of tumor lesions overexpressing sstr1. An efficient synthetic procedure for the preparation of the somatostatin analogue CH-275 and its conjugate DTPAGlu-Gly-CH-275, bearing the chelating agent DTPAGlu (DTPAGlu=N,N-bis[2-[bis(carboxy-ethyl)amino]ethyl]-L-glutamic acid) on the N-terminus, by solid-phase peptide synthesis and 9-fluorenylmethoxycarbonyl (Fmoc) chemistry, is here reported. Rapid and efficient labeling of DTPAGlu-Gly-CH-275 was achieved by addition of 111In(III) to the compound. Typical yields were greater than 97% as determined by reversed phase high performance liquid chromatography (HPLC) at specific activities in the range 4-9 GBq/micromol (100-250 Ci/mmol). A preliminary biological assay of the binding ability of 111In-DTPAGlu-Gly-CH-275 indicates, however, that the labeled compound does not display any specific interaction with somatostatin sstr1 receptors in the tested cell lines. To confirm this unexpected negative result, competition binding experiments were carried out, in which fixed tracer amounts of the 125I-labeled somatostatin-14 were incubated with the receptor-expressing cells in the presence of DTPAGlu-Gly-CH-275 or CH-275 at concentrations ranging from 10(-10) to 10(-3) M. While CH-275 shows a IC50 of 80 nM similar to that already found in displacement experiments on CHO-K1 sstr1-transfected cells, DTPAGlu-Gly-CH-275 displays instead very low or negligible affinity towards this receptor. The NMR solution characterization indicates that the presence of DTPAGlu does not influence the conformational and chemical features of the peptide moiety, thus suggesting that the loss in binding activity should be due to steric hindrance of either the chelating agent DTPAGlu or its indium complex.
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PMID:Peptide-chelating agent conjugate for selective targeting of somatostatin receptor type 1: synthesis and characterization. 1552 34

The structure-based design of peptide drugs requires the knowledge of the bioactive conformation. Studies on this receptor-bound 3D structure require linear or cyclic analogues with strongly reduced flexibility, but high biological activity, since only analogues with retained potency have preserved the bioactive conformation. Constrained amino acids containing double bonds or bulky substituents at the N(alpha)-, C(alpha)- and C(beta)-atom as well as at the aromatic ring atom were successfully applied to obtain potent and stable analogues of bradykinin and somatostatin, which due to their restricted conformation were suitable objects for conformational studies. Besides the generation of constrained cyclic analogues with improved biological and pharmacological properties, cyclic peptides were used as convenient models for the study of turn formations. Cyclization of the linear peptide bradykinin was performed by linking the N-terminus and the C-terminus, and in both bradykinin and somatostatin by cyclization using the amino acid side chains and by backbone cyclization. The later requires the introduction of N(alpha)-functionalised amino acids for ring closure which can be performed either through incorporation of N(alpha)-functionalised amino acids or dipeptide building units. Conformational analysis of a cyclic bradykinin analogue by means of NMR-studies together with molecular dynamics simulation led to a quasicyclic 3D structure with two turns and together with other 3D structures provided a pharmacophore model of bradykinin antagonists.
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PMID:Development of conformationally restricted analogues of bradykinin and somatostatin using constrained amino acids and different types of cyclization. 1554 78

The three-dimensional NMR structures of six analogues of somatostatin (SRIF) are described. These analogues with the amino acid 4-(N-isopropyl)-aminomethylphenylalanine (IAmp) at position 9 exhibit potent and highly selective binding to human SRIF subtype 1 receptors (sst(1)). The conformations reveal that the backbones of these analogues have a hairpin-like structure similar to the sst(2)-subtype-selective analogues. This structure serves as a scaffold for retaining a unique arrangement of the side chains of d-Trp(8), IAmp(9), Phe(7), and Phe(11) or m-I-Tyr(11) (m-I-Tyr = mono-iodo-tyrosine). The conformational preferences and results from biological analyses of these analogues(1,2) allow a detailed study of the structure-activity relationship of SRIF. The proposed consensus pharmacophore of the sst(1)-selective analogues requires a unique set of distances between an indole/2-naphthyl ring, an IAmp side chain, and two aromatic rings. This motif is necessary and sufficient to explain the binding affinities of all of the analogues studied and is distinct from the existing models suggested for sst(4) as well as sst(2)/sst(5) selectivity.
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PMID:Somatostatin receptor 1 selective analogues: 4. Three-dimensional consensus structure by NMR. 1565 66

The somatostatin analogue DOTATOC, DOTA-[Tyr(3)]octreotide, is used for in vivo diagnosis and targeted therapy of somatostatin-receptor-positive tumors. DOTATOC consists of a disulfide-bridged octapeptide, d-Phe(1)-Cys(2)-Tyr(3)-d-Trp(4)-Lys(5)-Thr(6)-Cys(7)-Thr(8)-ol, connected to the metal chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). Two metal complexes, Ga(III)- and Y(III)-DOTATOC, were reported to differ significantly in somatostatin receptor affinity and tumor uptake. Our (1)H and (13)C solution NMR data and modeling studies of both compounds are in agreement with a fast conformational equilibrium of the peptide part, as previously reported for octreotide itself. However, the different coordination geometry of Ga(3+) and Y(3+) (6-fold and 8-fold, respectively, as known from model compounds) causes pronounced differences for the d-Phe(1) residue. For Y(III)-DOTATOC this leads to two conformers exchanging slowly on the NMR time scale. From various NMR measurements, they could be identified as cis-trans isomers at the amide bond between DOTA chelator and first residue (d-Phe(1)H(N)) of the peptide.
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PMID:NMR studies reveal structural differences between the gallium and yttrium complexes of DOTA-D-Phe1-Tyr3-octreotide. 1574 93

An alanine scan performed in the 1970s suggested that Phe(6) and Phe(11) are required for the binding of somatostatin (SRIF-14). Molecular modeling studies and replacement of Phe(6) and Phe(11) with a cystine bridge affording ligands with the retention of high biological activity, however, led to the alternate conclusion that Phe(6) and Phe(11) stabilize the bioactive conformation of SRIF-14. Subsequent studies revealed that Phe(11) shields Phe(6) in a "herringbone" arrangement. More recently, a report from this laboratory demonstrated that Spartan 3-21G MO calculations can be invaluable in explaining SARs in medicinal chemistry. For example, the ability of benzene and indole rings to bind the Trp(8) binding pocket for SRIF-14 and the inability of pyrazine to do so was explained through differences in electrostatic potentials. To investigate the role of Phe(6) and Phe(11) more fully, we report here the synthesis of two analogues of D-Trp(8)-SRIF in which Phe(6) and Phe(11) were replaced by the pryazinylalanine congeners, respectively. The NMR spectra in D(2)O and the K(i)s fully support the proposition that Phe(11) stabilizes the bioactive conformation through pi-bonding or aromatic edge-to-face interaction and that pyrazinylalanine(6) can be shielded by Phe(11). The data also show unexpectedly that Phe(6), via the pi-bond, interacts with the receptor, consistent with the original interpretation of the alanine scan. Heretofore it had only been known that Lys(9) interacts with an aspartate anion of the receptor. These conclusions are supported by recent studies of Lewis et al. on the effects on K(i)s of Ala(6)-SRIF-14-amide at the five receptor subtargets. We also found that pyrazinylalanine(7)-D-Trp(8)-SRIF-14 does not bind, suggesting a repulsive interaction with the receptor. Taken together, our results not only validate predictions based on Spartan 3-21G MO analysis but also provide valuable information about the nature of the receptor interaction at the molecular level. Finally, the chirality of Trp(8) was unexpectedly found to have a striking effect on NMR spectra in methanol, especially at lower temperatures.
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PMID:Replacement of Phe6, Phe7, and Phe11 of D-Trp8-somatostatin-14 with L-pyrazinylalanine. Predicted and observed effects on binding affinities at hSST2 and hSST4. An unexpected effect of the chirality of Trp8 on NMR spectra in methanol. 1594 75


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