Design and discovery in the development of peptide analogs

Veber, Daniel F.

doi:10.1007/978-94-011-2264-1_1

Cited by 52 publications

(67 citation statements)

References 29 publications

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“…A three-dimensional structure of the cyclic hexapeptide 9 was generated from NMR studies of the corresponding Phe 7 cyclic peptide (16,21) using distance geometry methods to include the following features: a ␤IIЈ The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked ''advertisement'' in accordance with 18 U.S.C.…”

Section: Methodsmentioning

confidence: 99%

“…dipeptide of somatostatin is necessary for high-affinity binding (16) and have facilitated the development of potent analogs, including SMS 201-955 (Sandostatin or octreotide) which is clinically used for the treatment of acromegaly and certain endocrine tumors (17)(18)(19). We describe here strategies that were successful in designing small molecule subtype 2-selective agonists whose potencies on this receptor exceed somatostatin.…”

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confidence: 99%

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Synthesis and biological activities of potent peptidomimetics selective for somatostatin receptor subtype 2

Berk²,

Rohrer³

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

131

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A series of nonpeptide somatostatin agonists which bind selectively and with high affinity to somatostatin receptor subtype 2 (sst2) have been synthesized. One of these compounds, L-054,522, binds to human sst2 with an apparent dissociation constant of 0.01 nM and at least 3,000-fold selectivity when evaluated against the other somatostatin receptors. L-054,522 is a full agonist based on its inhibition of forskolin-stimulated adenylate cyclase activity in Chinese hamster ovary-K1 cells stably expressing sst2. L-054,522 has a potent inhibitory effect on growth hormone release from rat primary pituitary cells and glucagon release from isolated mouse pancreatic islets. Intravenous infusion of L-054,522 to rats at 50 g/kg per hr causes a rapid and sustained reduction in growth hormone to basal levels. The high potency and selectivity of L-054,522 for sst2 will make it a useful tool to further characterize the physiological functions of this receptor subtype.Somatostatin is widely distributed throughout the central nervous system and various endocrine tissues (1-3). Two biologically active forms of somatostatin are known, a 14-amino acid peptide and an N-terminal extended peptide with 28 amino acids (4 -6). Somatostatin has multiple functions, including modulation of growth hormone, insulin, glucagon, and gastric acid secretion (3, 7-10). Five somatostatin receptors (sst1-5) have been cloned and characterized (11)(12)(13)(14). All five receptors are members of the G protein-linked receptor family (15). Structure-function studies with a large number of peptidal analogs have shown that the Trp 8 -Lys 9 dipeptide of somatostatin is necessary for high-affinity binding (16) and have facilitated the development of potent analogs, including SMS 201-955 (Sandostatin or octreotide) which is clinically used for the treatment of acromegaly and certain endocrine tumors (17-19). We describe here strategies that were successful in designing small molecule subtype 2-selective agonists whose potencies on this receptor exceed somatostatin. Studies utilizing one of these subtype-selective somatostatin peptidomimetics, L-054,522, in both in vivo and in vitro experiments demonstate that somatostatin receptor subtype 2 (sst2) mediates the inhibition of growth hormone release from the rat anterior pituitary as well as glucagon from the rat pancreas. Insulin release is only inhibited at significantly higher concentrations of the compound. These results suggest possible therapeutic applications of selective sst2 agonists. Compound 4 was initially synthesized in a combinatorial library consisting of 20 diamines, 20 amino acids, and 79 amines. The diamines were linked to 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid functionalized Tentagel resin via urethane chemistry in a regiorandom way. 9-Fluorenylmethoxycarbonyl amino acids were coupled to the amine resins using standard 1,3-diisopropylcarbodiimide coupling. The 9-fluorenylmethoxycarbonyl groups were removed with piperidine and activated with p-nitrophenyl chloroformate before ...

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Synthesis and biological activities of potent peptidomimetics selective for somatostatin receptor subtype 2

Berk²,

Rohrer³

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

131

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“…Somatostatin has been employed in the treatment of acute gastrointestinal disorders, but its therapeutic use is limited by the very short in vivo half-life of 1 to 2min (Reichlin, 1983). Extensive activity studies on somatostatin and its derivatives (reviewed by Veber, 1992) have shown that the fragment -Phe7-TrpS-Lys9-Thr 1°-is essential for biological activity, and that this activity may be increased by replacing L-Trp 8 by its enantiomer D-Trp 8 (Rivier, Brown & Vale, 1975).…”

Section: Introductionmentioning

confidence: 99%

Structure of octreotide, a somatostatin analogue

Pohl¹,

Heine²,

Sheldrick³

et al. 1995

Acta Cryst D

122

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Octreotide, a synthetic somatostatin analogue, is an octapeptide with one disulfide bridge. Crystals of octreotide are orthorhombic, space group P212121, a = 18.458 (5), b = 30.009 (7), c = 39.705 (27) A, with three molecules of octapeptide, one ordered oxalate dianion and 52 water molecules in the asymmetric unit. Complete protonation of the NH2 groups (as assumed in the refinement) would require three oxalate dianions in the asymmetric unit for charge neutrality; a chemical analysis indicated that four are present. In either case they are so disordered that they cannot be distinguished from the water molecules. The 18 951 unique reflections (Rsy m = 0.026) used for structure solution and refinement were recorded with the EMBL imaging-plate scanner using synchrotron radiation. The structure was solved by Patterson interpretation, locating the three disulfide bridges, followed by tangent phase expansion and EFourier recycling. The anisotropic refinement against all F 2 data between 1.04 and 10.0 A resolution by blocked restrained full-matrix least-squares techniques converged to a conventional R index based on F of 0.084 [I > 2a(/) and 10.0 > d > 1.04 A] and wR2, the weighted R-index on F 2, of 0.246 (for all data). One peptide molecule adopts a flat ~-sheet structure; the other two possess different irregular backbone conformations, but are similar to each other. All three molecules have a distorted type II'/3-turn around the o-Trp-Lys region, but exhibit different sidechain conformations. The crystal structure is stabilized by a network of inter-and intramolecular hydrogen bonds.

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“…Indeed, for many GPCRs, the natural ligand can provide a good starting point, leading to useful pharmacophore models that can be used for identifying lead structures with novel scaffolds (6). These methods have been successfully applied for the discovery of peptide agonists to the somatostatin receptor (12) and for the discovery of nonpeptidic antagonists to the urotensin II receptor (13).…”

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confidence: 99%

G protein-coupled receptors:In silicodrug discovery in 3D

Becker¹,

Marantz²,

Shacham³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

164

158

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The application of structure-based in silico methods to drug discovery is still considered a major challenge, especially when the x-ray structure of the target protein is unknown. Such is the case with human G protein-coupled receptors (GPCRs), one of the most important families of drug targets, where in the absence of x-ray structures, one has to rely on in silico 3D models. We report repeated success in using ab initio in silico GPCR models, generated by the PREDICT method, for blind in silico screening when applied to a set of five different GPCR drug targets. More than 100,000 compounds were typically screened in silico for each target, leading to a selection of <100 ''virtual hit'' compounds to be tested in the lab. In vitro binding assays of the selected compounds confirm high hit rates, of 12-21% (full dose-response curves, K i < 5 M). In most cases, the best hit was a novel compound (New Chemical Entity) in the 1-to 100-nM range, with very promising pharmacological properties, as measured by a variety of in vitro and in vivo assays. These assays validated the quality of the hits as lead compounds for drug discovery. The results demonstrate the usefulness and robustness of ab initio in silico 3D models and of in silico screening for GPCR drug discovery.modeling ͉ in silico screening ͉ structure-based G protein-coupled receptors (GPCRs) are membraneembedded proteins, responsible for communication between the cell and its environment (1). As a consequence, many major diseases, such as hypertension, cardiac dysfunction, depression, anxiety, obesity, inflammation, and pain, involve malfunction of these receptors (2), making them among the most important drug targets for pharmacological intervention (3-5). Thus, whereas GPCRs are only a small subset of the human genome, they are the targets for Ϸ50% of all recently launched drugs (6). As targets of paramount importance, it is expected that drug discovery for GPCRs would benefit from the introduction of computational methodologies (7), especially as these methods can be used in conjunction with such experimental methods as high-throughput screening (8, 9), NMR, and crystallography (10).Unfortunately, GPCRs, like other membrane-embedded proteins, have characteristics that make their 3D structure extremely difficult to determine experimentally. To date, the only GPCR for which a 3D structure was determined by x-ray crystallography is bovine rhodopsin (11), which is unique among GPCRs in that its ligand, retinal, is covalently bound and that it responds to light rather than to ligand binding. Hence, in the case of GPCRs, the limited availability of structural data has forced the computational design of ligands to heavily rely on ligand-based techniques. Indeed, for many GPCRs, the natural ligand can provide a good starting point, leading to useful pharmacophore models that can be used for identifying lead structures with novel scaffolds (6). These methods have been successfully applied for the discovery of peptide agonists to the somatostatin receptor (12) and for...

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Design and discovery in the development of peptide analogs

Cited by 52 publications

References 29 publications

Synthesis and biological activities of potent peptidomimetics selective for somatostatin receptor subtype 2

Synthesis and biological activities of potent peptidomimetics selective for somatostatin receptor subtype 2

Structure of octreotide, a somatostatin analogue

G protein-coupled receptors:In silicodrug discovery in 3D

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