CORDIS - EU research results

Scaffold Based Supramolecular Architectures as Protein Epitope Mimetics for Biomedical Applications

Final Report Summary - 3D BIOMIMETICS (Scaffold Based Supramolecular Architectures as Protein Epitope Mimetics for Biomedical Applications)

Interactions of proteins with biological partners regulate essential cellular processes and their misregulation is often implicated in disease states. Proteins are generally poor drug candidates due to unfavourable pharmacokinetic profile derived from the low ability to penetrate biological membranes and the susceptibility to proteolytic degradation. On the other side, classical small-molecule drugs cannot act as agonists or antagonists of protein surface interactions and mimetics of protein active sites, due to the extended surface areas involved. Therefore, increasing attention has been recently devoted to fill the gap between small molecules and protein therapeutics and to design synthetic molecules of 500–5000 Da that can mimic the 3D structure of the part of a folded peptide involved in recognition events (protein epitope mimetics, PEMs). Nonetheless, it still remains truly challenging to transform 3D structural information into rationally designed synthetic mimetics with desired biological properties. The goal is to organize critical functional moieties, i.e. amino acid side chains or surrogates, into complementary spatial arrangements, as in bioactive structural elements and surfaces of proteins. Various levels of structural complexity can be considered, starting with the mimicry of individual secondary structure elements (turns, hairpins, β-structures and helices). Here, important advances have been achieved using either molecular constraints that stabilize specific conformations, or unnatural backbones (“foldamers”). Furthermore, recognition processes often involve multiple interactions that require multifaceted molecular architectures. Synthetic container compounds are modern tools of supramolecular chemistry and the resorcin[4]arene-based cavitands are common examples. There are many similarities between the deep cavitands and protein active sites, which have contributed to understanding the principles of molecular recognition in nature. Accordingly, resorcin[4]arene-based cavitands can also act as PEM platforms to present multiple functional elements in defined juxtapositions and sequester therapeutically important targets. Therefore, two classes of deep, water-soluble cavitands have been developed: Rim-aryl-functionalized resorcin[4]arene deep cavitand and Rim-urea-functionalized resorcin[4]arene deep cavitand. These cavitands readily binds lipophilic regions of specific and different physiological fats in aqueous solution; their development in supramolecular chemistry and biology augur well for their further practical applications in biomedicine. The synthetic procedures developed, after some adjustments at the late steps, allowed to produce water-soluble congeners bearing varied functional moieties, and enable for the preparation of alternative artificial receptors and PEM architectures.
Multivalent synthetic compounds emerged as valuable tool capable of performing a ‘glycoside cluster effect’ that provides high-affinity for specific receptors that play a key role in biological processes. Thus, sugar moieties have been attached in a multiple fashion to different backbones, including resorc[4]arenes and calix[4]arenes. Introduction of glycoside clusters in these structurally well-defined scaffolds has provided glyco-derivatives able to recognize specific guests and/or lectins for application as active compounds or molecular delivery systems. These systems have been developed as glycocalyx analogues that present a dense layer of a single type of carbohydrate units. In particular, some interesting examples of artificial glycoviral amphiphilic vectors have been reported to form micelle-like aggregates in water, called glycocluster nanoparticles, having four hydrophobic undecyl chains as feet and eight saccharide termini on the opposite sides of the bowl-shaped calix[4]resorcarene macrocycle. On the other hand, several resorc[4]arenes have been with feet that present chemical functionalities that allow for the attachment to a support. Here, resorcin[4]arene-based PEM platforms have been developed as “bipolar” macromolecular structures to present two different types of saccharide elements on the rims and feet, respectively. Such novel architectures can allow to significantly extend the structural and biomedical potential of resorc[4]arenes glyco-derivatives.

The project resulted in the generation of robust platform for proper special presentation of bio-relevant ligands (such as glycans), able to exploit the cluster effect that often is essential component of interaction of physiological and pathological relevance. Wide potential application in medicinal chemistry and diagnosis are envisaged, including the decoration of nanoparticles to favor targeting to specific raceptors.