RESUMO
The extensive research work in the exhilarating area of foldamers (artificial oligomers possessing well-defined conformation in solution) has shown them to be promising candidates in biomedical research and materials science. The post-modification approach is successful in peptides, proteins, and polymers to modulate their functions. To the best of our knowledge, site-selective post-modification of a foldamer affording molecules with different pendant functional groups within a molecular scaffold has not yet been reported. We demonstrate for the first time that late-stage site-selective functionalization of short hybrid oligomers is an efficient approach to afford molecules with diverse functional groups. In this article, we report the design and synthesis of hybrid peptides with repeating units of leucine (Leu) and 5-amino salicylic acid (ASA), regioselective post-modification, conformational analyses (based on solution-state NMR, circular dichroism and computational studies) and morphological studies of the peptide nanostructures. As a proof-of-concept, we demonstrate the applications of differently modified peptides as drug delivery agents, imaging probes, and anticancer agents. The novel feature of the work is that the difference in reactivity of two phenolic OH groups in short biomimetic peptides was utilized to achieve site-selective post-modification. It is challenging to apply the same approach to short α-peptides having a poor folding tendency, and their post-functionalization may considerably affect their conformation.
Assuntos
Peptídeos , Proteínas , Peptídeos/química , Conformação Molecular , Espectroscopia de Ressonância MagnéticaRESUMO
Protein fibrillation is linked to many devastating diseases including neurodegenerative disorders. Fluorescence probes play a significant role in the detection of amyloid aggregates, monitoring amyloid kinetics, and in the development of amyloid inhibitors. Despite the considerable progress in this area, the mechanism of amyloid fibril formation in vivo is not completely understood. Recent studies in amyloidosis indicate that oligomers and prefibrillar species are more cytotoxic than the fibrils. Hence, early diagnosis of fibrillation has high therapeutical relevance. The gold standard for amyloid staining is thioflavin-T and its major drawbacks are aggregation caused quenching and inability in the detection of oligomers. New amyloid staining probes with novel properties are highly desirable as they can give valuable insights into the complicated process and can replace conventional probes. Aggregation-induced emission probes (AIE-probes) with desirable features are promising candidates in protein fibrils imaging. AIE probes in staining different amyloid fibrils, monitoring amyloid kinetics, and early-stage conformers are reported. Other remarkable features are they can be modified as NIR probes, multifunctional probes, theranostic probes, and super-resolution imaging probes. We aim to provide a broad perspective on the progress attained with AIE probes in protein fibrils imaging and thereby emphasizing the scope of these smart probes in translative research.