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• W27754671 abstract "Id proteins (Id1-4) are negative regulators of several bHLH transcription factors; the 134-residue long Id2 protein additionally interacts with the retinoblastoma protein (pRb), thus representing an interesting target for cancer therapy based on the inhibition of protein-protein interactions.This work deals with the synthesis and conformational characterization of peptides derived from point mutations and N-/C-terminal truncations of Id2. The largest sequence that could be obtained by stepwise solid-phase peptide synthesis (SPPS) with Fmoc strategy, is a 75-residue long fragment (36-110) that was less helical than the isolated HLH domain and had propensity to aggregate. By CD analysis of an equimolar mixture of the sequence 36-110 with the N-terminus 1-35, non covalent interactions between the two peptides were detected, while the mixture of the HLH domain with the N-terminus was characterized by a stabilized helix structure maintained also upon aging.Id2 possesses a C-terminal nuclear export signal (NES, residues 103-119) responsible for the transport of Id2 from the nucleus to the cytoplasm. The Id2 segment 103-124 was synthesized and characterized in water/alcohol mixtures, displaying a beta-sheet conformation that quickly precipitated in amorphous aggregates. Introduction of an N-terminal tail bearing three lysines prevented aggressive precipitation and led to aggregates consisting of long beta-sheet fibrils that bound thioflavin T. When the positively charged tail was introduced at the C-terminus, the peptide was able to stay in solution for a longer time and to adopt a helical conformation and formed highly ordered aligned fibrils.The last part of this PhD work has been focused on the synthesis of peptidomimetics as potential modulators of protein-protein interactions. To this purpose, the unnatural amino acid 3-carboxy-cyclopentylglycine (Cpg) has been used as N,N-linker of two peptide fragments to form covalent homodimers. This has been done for Id helix-2 fragments, and the effect of both enantiomers of Cpg on the conformation has been investigated by CD spectroscopy. It was found that the Cpg-linked dimer of the Id1 helix-2 fragment 91-101 could interact with the native Id1 HLH motif, leading to helix stabilization or destabilization of the latter depending on the Cpg configuration. The Cpg-containing peptide was also tested on human vascular smooth muscle cells (VSMC) presenting a synthetic phenotype and preliminary data suggest that these peptides might influence the activity of the Id proteins. A second unnatural amino acid, 3,4-(aminomethano)proline (Amp), has been used in this work to synthesize alpha/gamma-alternating peptides (hexamers and octamers) containing both enantiomers of Amp. CD and NMR characterization show that the Amp in the (2S, 1�R, 3R, 4R)-configuration favors a helical backbone, as supported also by computational analysis, whereas the Amp in the (2R, 1�S, 3S, 4S)-configuration might induce a bend-like structure.The Amp amino acid has been used also as a proline analogue. CD spectroscopy data suggest that the substitution of LPro by the Amp unit with the S-configuration at the alpha-carbon may lead in pentapetides to a stabilization of a polyproline II conformation. The Amp unit with the R-configuration at the alpha-carbon seems to be superior in the stabilization of a turn motif. In conclusion, the synthetic and conformational studies on Id2 protein fragments and on oligomers containing new structurally constrained amino acid building blocks have provided interesting data concerning the usefulness of the solid phase methodology for the preparation of large polypeptides, the ability of a short Id2 fragment to form highly ordered fibrillar structures, and the development of novel backbone-modified peptides with ordered conformations, as valuable tools in the design of peptidomimetics and foldamers for biological applications." @default.
• W27754671 created "2016-06-24" @default.
• W27754671 creator A5028384781 @default.
• W27754671 date "2007-07-08" @default.
• W27754671 modified "2023-09-27" @default.
• W27754671 title "Synthesis and conformational analysis of polypeptides related to the inhibitor of the DNA binding and cell differentiation Id2" @default.
• W27754671 hasPublicationYear "2007" @default.
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