共查询到20条相似文献,搜索用时 15 毫秒
1.
β‐Peptides possess the ability to fold into secondary structure elements, and this property, together with resistance to biodegradation, makes these compounds interesting for pharmaceutical applications. Recently, a novel class of β‐peptides containing methylidene moieties was described. The GROMOS 53A6 force field was used to simulate the folding equilibrium of a β3‐hexapeptide with methylidene (CH2?) groups at all six CA‐atoms. Due to the rotational barriers induced by these methylidene groups, the helical secondary‐structure elements, normally found in β3‐peptides, are disfavored in this molecule. Simulations, started from fully extended and 314‐helical conformations, showed that the molecule adopts a complete 28‐helix for ca. 5% of the time and partial 28‐helical conformations for ca. 20% of the time. Yet, as suggested by experiments, the folding equilibrium is dominated by unfolded conformations. 相似文献
2.
The effect of elevated pressure on the conformational behavior of a β‐peptide heptamer ( 1 ) in MeOH solution was considered. The response of the peptide to elevated pressure was probed by means of molecular dynamics (MD) simulations, and described in atomic terms. The most‐striking features of the response are that the region of the ‘unfolded’ state of the peptide accessible at elevated pressure is narrow, and that thermal and pressure denaturation produce similar ‘unfolded’ states in the case of 1 . 相似文献
3.
The ability to design properly folded β‐peptides with specific biological activities requires detailed insight into the relationship between the amino acid sequence and the secondary and/or tertiary structure of the peptide. One of the most frequently used spectroscopic techniques for resolving the structure of a biomolecule is NMR spectroscopy. Because only signal intensities and frequencies are recorded in the experiment, a conformational interpretation of the recorded data is not straightforward, especially for flexible molecules. The occurrence of conformational and/or time averaging, and the limited amount and accuracy of experimental data hamper the precise conformational determination of a biomolecule. In addition, the relation between experimental observables with the underlying conformational ensemble is often only approximately known, thereby aggravating the difficulty of structure determination of biomolecules. The problematic aspects of structure refinement based on NMR nuclear Overhauser effect (NOE) intensities and 3J‐coupling data are illustrated by simulating a β‐octapeptide in explicit MeOH and H2O as solvents using three different force fields. NMR Data indicated that this peptide would fold into a 314‐helix in MeOH and into a hairpin in H2O. Our analysis focused on the conformational space visited by the peptide, on structural properties of the peptide, and on agreement of the MD trajectories with available NMR data. We conclude that 1) although the 314‐helical structure is present when the peptide is solvated in MeOH, it is not the only relevant conformation, and that 2) the NMR data set available for the peptide, when solvated in H2O, does not provide sufficient information to derive a single secondary structure, but rather a multitude of folds that fulfill the NOE data set. 相似文献
4.
Dongqi Wang Fabian Freitag Zrinka Gattin Hannah Haberkern Bernhard Jaun Magdalena Siwko Rounak Vyas Wilfred F. van Gunsteren Jožica Dolenc 《Helvetica chimica acta》2012,95(12):2562-2577
A molecular‐dynamics (MD) simulation study of two heptapeptides containing α‐ and β‐amino acid residues is presented. According to NMR experiments, the two peptides differ in dominant fold when solvated in MeOH: peptide 3 adopts predominantly β‐hairpin‐like conformations, while peptide 8 adopts a 14/15‐helical fold. The MD simulations largely reproduce the experimental data. Application of NOE atom? atom distance restraining improves the agreement with experimental data, but reduces the conformational sampling. Peptide 3 shows a variety of conformations, while still agreeing with the NOE and 3J‐coupling data, whereas the conformational ensemble of peptide 8 is dominated by one helical conformation. The results confirm the suitability of the GROMOS 54A7 force field for simulation or structure refinement of mixed α/β‐peptides in MeOH. 相似文献
5.
Grald Lelais Dieter Seebach Bernhard Jaun RaveendraI. Mathad Oliver Flgel Francesco Rossi Marino Campo Arno Wortmann 《Helvetica chimica acta》2006,89(3):361-403
The correlation between β2‐, β3‐, and β2,3‐amino acid‐residue configuration and stability of helix and hairpin‐turn secondary structures of peptides consisting of homologated proteinogenic amino acids is analyzed (Figs. 1–3). To test the power of Zn2+ ions in fortifying and/or enforcing secondary structures of β‐peptides, a β‐decapeptide, 1 , four β‐octapeptides, 2 – 5 , and a β‐hexadecapeptide, 10 , have been devised and synthesized. The design was such that the peptides would a) fold to a 14‐helix ( 1 and 3 ) or a hairpin turn ( 2 and 4 ), or form neither of these two secondary structures (i.e., 5 ), and b) carry the side chains of cysteine and histidine in positions, which will allow Zn2+ ions to use their extraordinary affinity for RS? and the imidazole N‐atoms for stabilizing or destabilizing the intrinsic secondary structures of the peptides. The β‐hexadecapeptide 10 was designed to a) fold to a turn, to which a 14‐helical structure is attached through a β‐dipeptide spacer, and b) contain two cysteine and two histidine side chains for Zn complexation, in order to possibly mimic a Zn‐finger motif. While CD spectra (Figs. 6–8 and 17) and ESI mass spectra (Figs. 9 and 18) are compatible with the expected effects of Zn2+ ions in all cases, it was shown by detailed NMR analyses of three of the peptides, i.e., 2, 3, 5 , in the absence and presence of ZnCl2, that i) β‐peptide 2 forms a hairpin turn in H2O, even without Zn complexation to the terminal β3hHis and β3hCys side chains (Fig. 11), ii) β‐peptide 3 , which is present as a 14‐helix in MeOH, is forced to a hairpin‐turn structure by Zn complexation in H2O (Fig. 12), and iii) β‐peptide 5 is poorly ordered in CD3OH (Fig. 13) and in H2O (Fig. 14), with far‐remote β3hCys and β3hHis residues, and has a distorted turn structure in the presence of Zn2+ ions in H2O, with proximate terminal Cys and His side chains (Fig. 15). 相似文献
6.
Raveendra I. Mathad Bernhard Jaun Oliver Flögel James Gardiner Markus Löweneck Jeroen D. C. Codée Peter H. Seeberger Dieter Seebach Michael K. Edmonds Florian H. M. Graichen Andrew D. Abell 《Helvetica chimica acta》2007,90(12):2251-2273
To further study the preference of the antiperiplanar (ap) conformation in α‐fluoro‐amide groups, two β‐peptides, 1 and 2 , containing a (2‐F)‐β3hAla and a (2‐F)‐β2hPhe residue, have been synthesized. Their NMR‐solution structures in CD3OH were determined and compared with those of non‐F‐substituted analogs, 3 and 4a . While we have found in a previous investigation (Helv. Chim. Acta 2005 , 88, 266) that a stereospecifically introduced F‐substituent in the central position of a β‐heptapeptide is capable of ‘breaking’ the 314‐helical structure by enforcing the F? C? C?O ap‐conformation, we could now demonstrate that the same procedure leads to a structure with the unfavorable ca. 90° F? C? C?O dihedral angle, enforced by the 314‐helical folding in a β‐tridecapeptide (cf. 1 ; Fig. 4). This is interpreted as a consequence of cooperative folding in the longer β‐peptide. A F‐substituent placed in the turn section of a β‐peptidic hairpin turn was shown to be in an ap‐arrangement with respect to the neighboring C?O bond (cf. 2 ; Fig. 7). Analysis of the non‐F‐substituted β‐tetrapeptides (with helix‐preventing configurations of the two central β2/β3‐amino acid residues) provides unusually tight hairpin structural clusters (cf. 3 and 4a ; Figs. 8 and 9). The skeleton of the β‐tetrapeptide H‐(R)β3hVal‐(R)β2hVal‐(R)β3hAla‐(S)β3hPhe‐OH ( 4a ) is proposed as a novel, very simple backbone structure for mimicking α‐peptidic hairpin turns. 相似文献
7.
Dongqi Wang Michael Friedmann Zrinka Gattin Bernhard Jaun Wilfred F. van Gunsteren 《Helvetica chimica acta》2010,93(8):1513-1531
We present a molecular‐dynamics simulation study of an α‐heptapeptide containing an α‐aminoisobutyric acid (=2‐methylalanine; Aib) residue, Val1‐Ala2‐Leu3‐Aib4‐Ile5‐Met6‐Phe7, and a quantum‐mechanical (QM) study of simplified models to investigate the propensity of the Aib residue to induce 310/α‐helical conformation. For comparison, we have also performed simulations of three analogues of the peptide with the Aib residue being replaced by L ‐Ala, D ‐Ala, and Gly, respectively, which provide information on the subtitution effect at C(α) (two Me groups for Aib, one for L ‐Ala and D ‐Ala, and zero for Gly). Our simulations suggest that, in MeOH, the heptapeptide hardly folds into canonical helical conformations, but appears to populate multiple conformations, i.e., C7 and 310‐helical ones, which is in agreement with results from the QM calculations and NMR experiments. The populations of these conformations depend on the polarity of the solvent. Our study confirms that a short peptide, though with the presence of an Aib residue in the middle of the chain, does not have to fold to an α‐helical secondary structure. To generate a helical conformation for a linear peptide, several Aib residues should be present in the peptide, either sequentially or alternatively, to enhance the propensity of Aib‐containing peptides towards the helical conformation. A correction of a few of the published NMR data is reported. 相似文献
8.
On the Use of a Supramolecular Coarse‐Grained Model for the Solvent in Simulations of the Folding Equilibrium of an Octa‐β‐peptide in MeOH and H2O
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Molecular dynamics (MD) simulation can give a detailed picture of conformational equilibria of biomolecules, but it is only reliable if the force field used in the simulation is accurate, and the sampling of the conformational space accessible to the biomolecule shows many (un)folding transitions to allow for precise averages of observable quantities. Here, the use of coarse‐grained (CG) solvent MeOH and H2O models to speed up the sampling of the conformational equilibria of an octa‐β‐peptide is investigated. This peptide is thought to predominantly adopt a 314‐helical fold when solvated in MeOH, and a hairpin fold when solvated in H2O on the basis of the NMR data. Various factors such as the chirality of a residue, a force‐field modification for the solute, coarse‐graining of the solvent model, and an extension of the nonbonded interaction cut‐off radius are shown to influence the simulated conformational equilibria and the agreement with the experimental NMR data for the octa‐β‐peptide. 相似文献
9.
Free‐energy differences govern the equilibrium between bound and unbound states of a host and its guest molecules. The understanding of the underlying entropic and enthalpic contributions, and their complex interplay are crucial for the design of new drugs and inhibitors. In this study, molecular dynamics (MD) simulations were performed with inclusion complexes of α‐cyclodextrin (αCD) and three monosubstituted benzene derivatives to investigate host–guest binding. αCD Complexes are an ideal model system, which is experimentally and computationally well‐known. Thermodynamic integration (TI) simulations were carried out under various conditions for the free ligands in solution and bound to αCD. The two possible orientations of the ligand inside the cavity were investigated. Agreement with experimental data was only found for the more stable orientation, where the substituent resides inside the cavity. The better stability of this conformation results from stronger Van der Waals interactions and a favorable antiparallel host–guest dipole–dipole alignment. To estimate the entropic contributions, simulations were performed at three different temperatures (250, 300, and 350 K) and using positional restraints for the host. The system was found to be insensitive to both factors, due to the large and symmetric cavity of αCD, and the nondirectional nature of the host–guest interactions. 相似文献
10.
Dieter Seebach Bernhard Jaun Radovan Sebesta RaveendraI. Mathad Oliver Flgel Michael Limbach Holger Sellner Sylvain Cottens 《Helvetica chimica acta》2006,89(9):1801-1825
Twelve peptides, 1 – 12 , have been synthesized, which consist of alternating sequences of α‐ and β‐amino acid residues carrying either proteinogenic side chains or geminal dimethyl groups (Aib). Two peptides, 13 and 14 , containing 2‐methyl‐3‐aminobutanoic acid residues or a ‘random mix’ of α‐, β2‐, and β3‐amino acid moieties were also prepared. The new compounds were fully characterized by CD (Figs. 1 and 2), and 1H‐ and 13C‐NMR spectroscopy, and high‐resolution mass spectrometry (HR‐MS). In two cases, 3 and 14 , we discovered novel types of turn structures with nine‐ and ten‐membered H‐bonded rings forming the actual turns. In two other cases, 8 and 11 , we found 14/15‐helices, which had been previously disclosed in mixed α/β‐peptides containing unusual β‐amino acids with non‐proteinogenic side chains. The helices are formed by peptides containing the amino acid moiety Aib in every other position, and their backbones are primarily not held together by H‐bonds, but by the intrinsic conformations of the containing amino acid building blocks. The structures offer new possibilities of mimicking peptide–protein and protein–protein interactions (PPI). 相似文献
11.
Atsushi Suenaga Dr. Tetsu Narumi Dr. Noriyuki Futatsugi Dr. Ryoko Yanai Yousuke Ohno Dr. Noriaki Okimoto Dr. Makoto Taiji Dr. 《化学:亚洲杂志》2007,2(5):591-598
Short peptides that fold into β‐hairpins are ideal model systems for investigating the mechanism of protein folding because their folding process shows dynamics typical of proteins. We performed folding, unfolding, and refolding molecular dynamics simulations (total of 2.7 μs) of the 10‐residue β‐hairpin peptide chignolin, which is the smallest β‐hairpin structure known to be stable in solution. Our results revealed the folding mechanism of chignolin, which comprises three steps. First, the folding begins with hydrophobic assembly. It brings the main chain together; subsequently, a nascent turn structure is formed. The second step is the conversion of the nascent turn into a tight turn structure along with interconversion of the hydrophobic packing and interstrand hydrogen bonds. Finally, the formation of the hydrogen‐bond network and the complete hydrophobic core as well as the arrangement of side‐chain–side‐chain interactions occur at approximately the same time. This three‐step mechanism appropriately interprets the folding process as involving a combination of previous inconsistent explanations of the folding mechanism of the β‐hairpin, that the first event of the folding is formation of hydrogen bonds and the second is that of the hydrophobic core, or vice versa. 相似文献
12.
Krishnayan Basuroy Appavu Rajagopal Dr. Srinivasarao Raghothama Prof. Narayanaswamy Shamala Prof. Padmanabhan Balaram 《化学:亚洲杂志》2012,7(7):1671-1678
The effect of gem‐dialkyl substituents on the backbone conformations of β‐amino acid residues in peptides has been investigated by using four model peptides: Boc‐Xxx‐β2,2Ac6c(1‐aminomethylcyclohexanecarboxylic acid)‐NHMe (Xxx=Leu ( 1 ), Phe ( 2 ); Boc=tert‐butyloxycarbonyl) and Boc‐Xxx‐β3,3Ac6c(1‐aminocyclohexaneacetic acid)‐NHMe (Xxx=Leu ( 3 ), Phe ( 4 )). Tetrasubstituted carbon atoms restrict the ranges of stereochemically allowed conformations about flanking single bonds. The crystal structure of Boc‐Leu‐β2,2Ac6c‐NHMe ( 1 ) established a C11 hydrogen‐bonded turn in the αβ‐hybrid sequence. The observed torsion angles (α(?≈?60°, ψ≈?30°), β(?≈?90°, θ≈60°, ψ≈?90°)) corresponded to a C11 helical turn, which was a backbone‐expanded analogue of the type III β turn in αα sequences. The crystal structure of the peptide Boc‐Phe‐β3,3Ac6c‐NHMe ( 4 ) established a C11 hydrogen‐bonded turn with distinctly different backbone torsion angles (α(?≈?60°, ψ≈120°), β(?≈60°, θ≈60°, ψ≈?60°)), which corresponded to a backbone‐expanded analogue of the type II β turn observed in αα sequences. In peptide 4 , the two molecules in the asymmetric unit adopted backbone torsion angles of opposite signs. In one of the molecules, the Phe residue adopted an unfavorable backbone conformation, with the energetic penalty being offset by a favorable aromatic interaction between proximal molecules in the crystal. NMR spectroscopy studies provided evidence for the maintenance of folded structures in solution in these αβ‐hybrid sequences. 相似文献
13.
Andreas A. Deeg Michael S. Rampp Alexander Popp Bert M. Pilles Dr. Tobias E. Schrader Prof. Dr. Luis Moroder Prof. Dr. Karin Hauser Prof. Dr. Wolfgang Zinth 《Chemistry (Weinheim an der Bergstrasse, Germany)》2014,20(3):694-703
Conformational changes in proteins and peptides can be initiated by diverse processes. This raises the question how the variation of initiation mechanisms is connected to differences in folding or unfolding processes. In this work structural dynamics of a photoswitchable β‐hairpin model peptide were initiated by two different mechanisms: temperature jump (T‐jump) and isomerization of a backbone element. In both experiments the structural changes were followed by time‐resolved IR spectroscopy in the nanosecond to microsecond range. When the photoisomerization of the azobenzene backbone switch initiated the folding reaction, pronounced absorption changes related to folding into the hairpin structure were found with a time constant of about 16 μs. In the T‐jump experiment kinetics with the same time constant were observed. For both initiation processes the reaction dynamics revealed the same strong dependence of the reaction time on temperature. The highly similar transients in the microsecond range show that the peptide dynamics induced by T‐jump and isomerization are both determined by the same mechanism and exclude a downhill‐folding process. Furthermore, the combination of the two techniques allows a detailed model for folding and unfolding to be presented: The isomerization‐induced folding process ends in a transition‐state reaction scheme, in which a high energetic barrier of 48 kJ mol?1 separates unfolded and folded structures. 相似文献
14.
The ability to design well‐folding β‐peptides with a specific biological activity requires detailed insight into the relationship between the β‐amino acid sequence and the three‐dimensional structure of the peptide. Here, we present a molecular‐dynamics (MD) study of the influence of a variation of a side chain on the folding equilibrium of a β‐heptapeptide that folds into a 314‐helical structure. The side chain of the 5th residue, a valine, was changed into five differently branched side chains of different lengths and polarity, Ala, Leu, Ile, Ser, and Thr. Two computational techniques, long‐time MD simulations and the one‐step perturbation method, were used to obtain free enthalpies of folding. The simulations show that all six peptides exhibit similar folding behavior, and that their dominant fold is the same, i.e., a 314‐helix. Despite the similarities of their structural properties, a small stabilization effect of ca. 2 kJ mol?1 on the folding equilibrium of the 314‐helical structure due to a branching Cγ‐atom in the β3‐side chain is observed. These results confirm those of previous circular dichroism (CD) studies. The length of side chain and its polarity seem to have no apparent (de)stabilization effect. Application of the cost‐effective one‐step perturbation method to predict free‐enthalpy differences appeared to yield an overall accuracy of about kBT, which is not sufficient to detect the small stabilization effect. 相似文献
15.
Anthony Linden J. E. Florian Magirius Heinz Heimgartner 《Acta Crystallographica. Section C, Structural Chemistry》2020,76(1):1-9
Depsipeptides and cyclodepsipeptides are analogues of the corresponding peptides in which one or more amide groups are replaced by ester functions. Reports of crystal structures of linear depsipeptides are rare. The crystal structures and conformational analyses of four depsipeptides with an alternating sequence of an α,α‐disubstituted α‐amino acid and an α‐hydroxy acid are reported. The molecules in the linear hexadepsipeptide amide in (S)‐Pms‐Acp‐(S)‐Pms‐Acp‐(S)‐Pms‐Acp‐NMe2 acetonitrile solvate, C47H58N4O9·C2H3N, ( 3b ), as well as in the related linear tetradepsipeptide amide (S)‐Pms‐Aib‐(S)‐Pms‐Aib‐NMe2, C28H37N3O6, ( 5a ), the diastereoisomeric mixture (S,R)‐Pms‐Acp‐(R,S)‐Pms‐Acp‐NMe2/(R,S)‐Pms‐Acp‐(R,S)‐Pms‐Acp‐NMe2 (1:1), C32H41N3O6, ( 5b ), and (R,S)‐Mns‐Acp‐(S,R)‐Mns‐Acp‐NMe2, C30H37N3O6, ( 5c ) (Pms is phenyllactic acid, Acp is 1‐aminocyclopentanecarboxylic acid and Mns is mandelic acid), generally adopt a β‐turn conformation in the solid state, which is stabilized by intramolecular N—H…O hydrogen bonds. Whereas β‐turns of type I (or I′) are formed in the cases of ( 3b ), ( 5a ) and ( 5b ), which contain phenyllactic acid, the torsion angles for ( 5c ), which incorporates mandelic acid, indicate a β‐turn in between type I and type III. Intermolecular N—H…O and O—H…O hydrogen bonds link the molecules of ( 3a ) and ( 5b ) into extended chains, and those of ( 5a ) and ( 5c ) into two‐dimensional networks. 相似文献
16.
17.
Krishnayan Basuroy Vasantham Karuppiah Narayanaswamy Shamala Padmanabhan Balaram 《Helvetica chimica acta》2012,95(12):2589-2603
Backbone alkylation has been shown to result in a dramatic reduction in the conformational space that is sterically accessible to α‐amino acid residues in peptides. By extension, the presence of geminal dialkyl substituents at backbone atoms also restricts available conformational space for β and γ residues. Five peptides containing the achiral β2,2‐disubstituted β‐amino acid residue, 1‐(aminomethyl)cyclohexanecarboxylic acid (β2,2Ac6c), have been structurally characterized in crystals by X‐ray diffraction. The tripeptide Boc‐Aib‐β2,2Ac6c‐Aib‐OMe ( 1 ) adopts a novel fold stabilized by two intramolecular H‐bonds (C11 and C9) of opposite directionality. The tetrapeptide Boc‐[Aib‐β2,2Ac6c]2‐OMe ( 2 ) and pentapeptide Boc‐[Aib‐β2,2Ac6c]2‐Aib‐OMe ( 3 ) form short stretches of a hybrid αβ C11 helix stabilized by two and three intramolecular H‐bonds, respectively. The structure of the dipeptide Boc‐Aib‐β2,2Ac6c‐OMe ( 5 ) does not reveal any intramolecular H‐bond. The aggregation pattern in the crystal provides an example of an extended conformation of the β2,2Ac6c residue, forming a ‘polar sheet’ like H‐bond. The protected derivative Ac‐β2,2Ac6c‐NHMe ( 4 ) adopts a locally folded gauche conformation about the Cβ? Cα bonds (θ=?55.7°). Of the seven examples of β2,2Ac6c residues reported here, six adopt gauche conformations, a feature which promotes local folding when incorporated into peptides. A comparison between the conformational properties of β2,2Ac6c and β3,3Ac6c residues, in peptides, is presented. Backbone torsional parameters of H‐bonded αβ/βα turns are derived from the structures presented in this study and earlier reports. 相似文献
18.
This article describes the stereo‐ and regioselectivity of the deoxofluorination of N‐terminal dipeptides bearing a serine residue to generate, after rearrangement, α‐fluoro‐β‐amine‐terminated dipeptides. The ratio of the rearranged α‐fluorinated regioisomer is increased, relative to the non‐rearranged β‐fluoro isomer, with N‐alkylated amides. Otherwise, an intramolecular H‐bond between the free amine and the amide NH suppresses formation of the key aziridinium intermediate required for α‐fluorination. N‐Methyl and N‐allyl amides give exclusively α‐fluorination products. Subsequent deprotection of the N‐allyl amide to give a α‐fluoro‐β‐amino dipeptide product is demonstrated. 相似文献
19.
20.
Dieter Seebach Estelle Dubost Raveendra I. Mathad Bernhard Jaun Michael Limbach Markus Löweneck Oliver Flögel James Gardiner Stefania Capone Albert K. Beck Hans Widmer Daniel Langenegger Dominique Monna Daniel Hoyer 《Helvetica chimica acta》2008,91(9):1736-1786
Cyclo‐β‐tetrapeptides are known to adopt a conformation with an intramolecular transannular hydrogen bond in solution. Analysis of this structure reveals that incorporation of a β2‐amino‐acid residue should lead to mimics of ‘α‐peptidic β‐turns’ (cf. A, B, C ). It is also known that short‐chain mixed β/α‐peptides with appropriate side chains can be used to mimic interactions between α‐peptidic hairpin turns and G protein‐coupled receptors. Based on these facts, we have now prepared a number of cyclic and open‐chain tetrapeptides, 7 – 20 , consisting of α‐, β2‐, and β3‐amino‐acid residues, which bear the side chains of Trp and Lys, and possess backbone configurations such that they should be capable of mimicking somatostatin in its affinity for the human SRIF receptors (hsst1–5). All peptides were prepared by solid‐phase coupling by the Fmoc strategy. For the cyclic peptides, the three‐dimensional orthogonal methodology (Scheme 3) was employed with best success. The new compounds were characterized by high‐resolution mass spectrometry, NMR and CD spectroscopy, and, in five cases, by a full NMR‐solution‐structure determination (in MeOH or H2O; Fig. 4). The affinities of the new compounds for the receptors hsst1–5 were determined by competition with [125I]LTT‐SRIF28 or [125I] [Tyr10]‐CST14. In Table 1, the data are listed, together with corresponding values of all β‐ and γ‐peptidic somatostatin/Sandostatin® mimics measured previously by our groups. Submicromolar affinities have been achieved for most of the human SRIF receptors hsst1–5. Especially high, specific binding affinities for receptor hsst4 (which is highly expressed in lung and brain tissue, although still of unknown function!) was observed with some of the β‐peptidic mimics. In view of the fact that numerous peptide‐activated G protein‐coupled receptors (GPCRs) recognize ligands with turn structure (Table 2), the results reported herein are relevant far beyond the realm of somatostatin: many other peptide GPCRs should be ‘reached’ with β‐ and γ‐peptidic mimics as well, and these compounds are proteolytically and metabolically stable, and do not need to be cell‐penetrating for this purpose (Fig. 5). 相似文献