Grafting Aminocyclopentane Carboxylic Acids onto the RGD Tripeptide Sequence Generates Low Nanomolar αVβ3/αVβ5Integrin Dual Binders
Giovanni CasiraghiGloria RassuLuciana AuzzasPaola BurredduE GaetaniLucia BattistiniFranca ZanardiClaudio CurtiGiuseppe NicastroLaura BelvisiIlaria MottoMassimo CastorinaGiuseppe GianniniClaudio Pisano
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Eleven γ-aminocyclopentane carboxylic acid (Acpca) platforms, including four dihydroxy representatives (19−22), three hydroxy analogues (34−36), and four deoxy derivatives (30−33), were prepared in a chiral nonracemic format. These simple units were then grafted onto an Arg-Gly-Asp (RGD) tripeptide framework by a mixed solid phase/solution protocol delivering an ensemble of 11 macrocyclic analogues of type cyclo-[-Arg-Gly-Asp-Acpca-], 1−11. The individual compounds were evaluated for their binding affinity toward the αVβ3 and αVβ5 integrin receptors. The analogue 10 exhibited a very interesting activity profile (IC50/αVβ3 = 1.5 nM; IC50/αVβ5 = 0.59 nM), comparable to that of reference compounds EMD121974 and ST1646. Closely related congeners 6, 8, and 9 also proved to be excellent dual binders with activity levels in the low nanomolar range. The three-dimensional (3D) NMR solution structures were determined, and docking studies to X-ray crystal structure of the extracellular segment of integrin αVβ3 in complex with the reference compound EMD121974 were performed on selected analogues to elucidate the interplay between structure and function in these systems and to evidence the subtle bases for receptorial recognition. The results prove that the principle of isosteric dipeptide replacement for peptidomimetics design and synthesis can be violated, without detriment to the development of highly effective integrin binders.Keywords:
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A simple, dye(R)-labeled and conformationally restricted ionophore 2 was prepared and screened for peptide binding using solid-supported combinatorial libraries of 24 389 protected and unprotected tripeptides. The ionophore was found generally to bind unhindered cationic peptides having arginines or N-terminal glycines. The podand was particularly selective in the case of unprotected tripeptides and was able to selectively bind a single tripeptide (l-Arg-l-Phe-d-Asp) from the unprotected ∼24000-member tripeptide library. These results indicate that relatively simple organic molecules can make highly sequence-selective receptors for tripeptides. Structural features of such receptors are discussed.
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Abstract: Conformational study of RGD tripeptides in the nonhydrated and hydrated states was carried out using an empirical potential function ECEPP/3 and the hydration shell model in order to investigate preferred conformations and factors responsible for their stability. RGD tripeptides in the nonhydrated and hydrated states can be interpreted as existing as an ensemble of feasible conformations rather than as a single dominant conformation from the analysis of distributions of backbone conformations, hydrogen bonds and β‐turns. The different distributions of conformations for the neutral and zwitterionic RGD tripeptides in both states may indicate that the conformation of the RGD tripeptide is liable to depend on solvent polarity and pH values. β‐Turn populations for the neutral tripeptide in both states are reasonably consistent with NMR measurements on linear RGD‐containing peptides. The degradation of RGD tripeptide seems to be attributed mainly to the hydrogen bonds between the Asp side‐chain and the backbone of Asp residue or C‐terminal NHMe group, rather than to the flexible backbones of Gly and Asp residues.
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Early research has shown that many neurodegenerative diseases are associated with the absence of a short and natural tripeptide sequence, Lys-Phe-Gly (KFG). Herein we report results of both experiments and extensive MD simulations of this tripeptide to understand the self-assembly and morphology as a function of its concentration. Morphologies of the aggregates formed by the tripeptide at low concentration (vesicles), and at high concentration (nanotubes) are studied by several independent 3 μs long Martini coarse-graining MD simulation runs. Further, prediction from MD at still higher concentrations about the formation of rectangular blocks, reported for the first time, has been verified through laboratory experiments. Thus, the computational studies performed are in agreement with the experimental findings observed in our laboratory and a complete control over the formation of various nanostructures is achieved simply by changing the concentration of a short and naturally conserved tripeptide.
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In order to test the specificity of the natural Delta-Sleep-Inducing-Peptide (DSIP), a tripeptide with the same N-terminal amino acid was synthesized. The synthesis of the new tripeptide L-Trp-L-Ser-L-Glu was carried out by the method of the mixed anhydride. Protecting groups were all oxygen-bound benzyl groups. The physical-chemical data of the newly synthesized peptides are reported. The biological activity of the tripeptide was assayed by intraventricular infusion in the rabbit under the same conditions as for the DSIP. The effects of the tripeptide on the EEG could not duplicate those of DSIP which induced a marked increase of delta activity, typical for orthodox 'Slow Wave Sleep' (SWS).
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Thirty two synthetic tripeptides structurally related both to thyrotropin releasing hormone (TRH) and anorexogenic tripeptide (Glp-His-Gly-OH) were investigated for anorexogenic effect in rats. While the two endogenous peptides, TRH and Glp-His-Gly-OH, were ineffective in rats deprived of food for 96 hours when they were administered intracerebroventricularly, some of the synthetic analogues showed significant food intake reducing effect under the same conditions. This anorexogenic effect of the tripeptides is similar--though much weaker--to that of satietin, a highly potent anorexogenic glycopeptide in human and mammalian serum. These tripeptides were ineffective when they were administered intravenously.
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Arm: to search for a protocol for synthesis of tripeptide. Method: dicarbonyl dichloride method was used to synthesize tripep-tides. Results: three kinds of tripeptides were successfully synthesized and identified by mass spectrometry, infrared spectrum, nuclear magnetic resonance and element analysis respectively. Conclusion: the protocol developed by the author is useful and suitable for synthesis of tripeptides from acidic aminoacids.
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