Wspólnotowy Serwis Informacyjny Badan i Rozwoju - CORDIS

FP7

RELOADPEPSYN Streszczenie raportu

Project ID: 625555
Źródło dofinansowania: FP7-PEOPLE
Kraj: United Kingdom

Final Report Summary - RELOADPEPSYN (A Reloadable Molecular Peptide Synthesizer)

The aim of this project is to construct a synthetic molecular machine that is capable of performing a complex task, chemical synthesis, far beyond the current state-of-the-art. Our target is to mimic multiple translation, the process through which protein is synthesized on the mRNA template by the ribosome. By taking advantage of a reloadable track I intend to synthesize peptide chains without erasing the information intrinsic to the track. To achieve this ambitious task through the action of a wholly artificial molecular machine system, I propose to utilize [2]rotaxanes in which the macrocycle components act as both a catalyst and a molecular transporter, abstracting bulky building blocks from a sequence-specific ‘thread’ and transporting them in turn to the next building block before mediating the formation of a new covalent bond between them. The design is such that the macrocycle is forced to approach each building block in sequence, and is unable to pass until the building block is transferred, imparting sequential integrity to the oligomer synthesis. The mechanically interlocked nature of the rotaxane ensures processivity during the machine’s operation. Although biology uses threaded molecular architectures to transfer chemical information during sequence-specific oligomer and polymer assembly, such effects are yet to be improved in artificial small-molecule systems.

After series of optimization reactions, target machine was synthesized and characterized using modified macrocycle (M) and stopper moieties T1 and T2 as planned in section B4-part 1.2, Scheme 3 of the proposal. Pyridiyl moiety on T1 was replaced with hydrazide in order to be able to load the amino acid via another hydrazone linkage. This optimized design is preferred due to unstable nature of original metal complex in the presence of thiolate. Rotaxane formation using copper-catalysed Huisgen cycloaddition, deprotection of the machine gave decent yields and characterised by various 2D NMR spectra and High Resolution Mass Spectrometry. The machine was loaded with two amino acids under acidic conditions and operated in the presence of base (triethylamine) and reducing agent, Tris(2-carboxyethyl)phosphine hydrochloride. Analysis of the crude operation product by High Resolution Mass Spectrometry indicates that two amino acids are successfully incorporated to the growing chain and Tandem Mass Spectroscopy analysis proves that these amino acids are in correct order. These findings suggest that information on the track is successfully used to load each amino acid to specifıc region of the machine.

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Kontakt

Liz Fay, (EU Funding and Development Manager)
Tel.: +441612757114
Faks: +441612757114
Adres e-mail
Numer rekordu: 184480 / Ostatnia aktualizacja: 2016-06-24