Molecular receptors as tools for the development of novel stimuli-responsive peptide systems and molecular recognition of relevant biological targets

Abstract

This thesis focuses on the use of two types of molecular receptors, two cucurbit[n]urils and a polycationic cyclophane, for two distinct purposes: the development of new supramolecular stimuli-responsive systems, and the targeting of G-quadruplex DNA structures. First, a novel stimuli-responsive artificial transcription factor was developed. The new peptide conjugate is based on the basic region of the GCN4 transcription factor modified with a 4,4′-bipyridinium moiety and forms a supramolecular dimer in the presence of cucurbit[8]uril. Importantly, this supramolecular dimer specifically recognizes its target DNA sequence, and this binding can be reversibly switched by external stimuli. Next, a new redox-responsive tripeptide motif was developed containing an N-terminal cysteine residue modified in the side chain with an aromatic moiety through a disulfide bond. Significantly, this tripeptide can form a binary inclusion complex with cucurbit[7]uril that can be disrupted by a reducing agent. Finally, the activity of the Red box as a selective G-quadruplex binder was demonstrated. Remarkably, this cyclophane shows a higher affinity for G-quadruplex sequences compared to model double-stranded DNA sequences and, in particular, for c-MYC and c-KIT2 G-quadruplexes. Remarkably, biological studies have shown that the Red box significantly reduces the expression levels of the c-MYC protooncogene.