SUZUKI PEPTIDES · Peptide ligands with restricted mobility through a Suzuki reaction: design, synthesis and evaluation
7РП — „Хора“ (Действия „Мария Кюри“)
- Период
- 2009-10-01 → 2012-09-30
- Финансиране от ЕС
- 45 000 €
- Участници
- 1
- Схема
- MC-ERG
Линиите свързват координатора с партньорите.
Накратко на български
Циклични пептиди с твърда структура, създадени чрез химическа реакция „Сузуки“, се разработват като специфични молекулярни свързачи. Тези структури помагат за по-доброто разпознаване и свързване с повърхностите на протеините в организма.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Peptide ligands with restricted mobility through a Suzuki reaction: Design, synthesis and evaluation
Natural cyclic peptides containing an aryl-aryl bond are abundant, diverse and constitute a heterogeneous group, including compounds which show antimicrobial or cytotoxic activities. A common feature of all of them is the rigidity imposed by the presence of the biaryl bridge. The biaryl system also provides a site for aromatic-aromatic or p-cation interactions with the residues present on protein surfaces. This last structural feature has so far not been exploited in the design of peptide ligands for protein surface recognition. With this in mind, the scope of our project was to prepare cyclic peptide ligands which were further constrained by means of a biaryl bond. We envision this type of biaryl-containing bicyclic peptides as constrained scaffolds, which can be customised according to the corresponding target. With this in mind, we have developed a synthetic methodology for the preparation of model biaryl bicyclic peptides, which is based on an intramolecular Suzuki-Miyaura reaction. Different synthetic approaches have been explored, regarding solution versus on-resin peptide modification, protection schemes and solid-supports. Our optimised procedure consists in the on-resin modification of the linear peptide solid-phase peptide synthesis, on resin borylation and Suzuki-Miyaura reaction, combined with head-to-tail cyclisation in solution. This way, several bicyclic biaryl peptides have been prepared, applying this synthetic procedure to other model sequences, incorporating side-chain functionalities. To the best of our knowledge, this is the first example of biaryl bicyclic peptides obtained through an on-resin intramolecular Suzuki-Miyaura reaction. Furthermore, the developed synthetic methodology can be applied for the preparation of tailored sequences for the interaction with selected targets.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
The aim of this research proposal is the application of the Suzuki-Miyaura reaction to the synthesis of peptidic libraries with restricted mobility. Specifically, we envision the synthesis of a family of cyclic peptides that will contain a biaryl bond, to further restrain their conformation. This biaryl bond will be obtained through a Suzuki-Miyaura set of reactions between two aromatic amino acid derivatives in the sequence. Initially, the reaction conditions will be optimized on simple models: the order in which the bicyclic peptides should be assembled, solid vs. solution-phase, Suzuki-Miyaura reaction conditions…Once the synthesis has been optimized, several peptide libraries will be prepared, progressively increasing the synthetic challenge and including D- and non-proteinogenic amino acids. The ultimate goal of the project is to obtain new series of peptides which will act as ligands of certain protein surfaces (POP, DPP-IV and VEGF), for which they will have been designed. The sequences to be synthesized will be first decided on rational design basis assisted through evolutionary algorithms and, later, based on the results obtained for the interaction with the therapeutic target. Special attention will be placed on the conformational study of such constrained molecules. The interaction of the new peptides with the proteins surfaces, as well as their ADME properties will be evaluated through different methods.
Оригинален текст от CORDIS (на английски).
Участници
- FUNDACIO INSTITUT DE RECERCA BIOMEDICA (IRB BARCELONA) · BarcelonaКоординаторИспания
Връзки
Данни: CORDIS, © Европейски съюз