The first globular peptide fullerene hybrid for the recognition of cancer receptors

CIQUS scientists in collaboration with UCM researchers synthesize the first fully substituted peptide-fullerene adduct for the selective binding with a receptor involved in cancer. The work have now been published in Angewandte Chmemie journal.

In cancer metastasis, malignant cells from a primary tumor can spread to other tissues. To get attached into these new tissues, circulating tumors cells can get attached to protein receptors such as the selectins. For example, the E-selectin, a protein receptor that uses multivalent recognition to selectively interact with its ligands. The natural ligand of these receptors can be complex glycan molecules, which are very difficult to synthesize in the laboratory. Therefore, the design of new inhibitors for such protein receptors is an area of great therapeutic interest.

Peptides are biomolecular polymers that can be easily synthesized in the chemistry laboratory by solid phase synthesis. The discovery of the phage-display technology, Nobel prize in 2018, has allowed the quick identification of high affinity peptide binders for any protein receptor. Therefore, the potential multivalent presentation of the chemical information codified in peptides constitutes a highly powerful strategy for the potential selective recognition of proteins of interest.

The fullerene is the carbon allotrope, or the only carbon molecule, with the shape of a soccer ball. This carbon allotrope showed interesting molecular properties and applicability in different fields such as electronics, energy conversion and also biomedicine. In biology, the globular shape of the fullerene makes it an ideal candidate for the three-dimensional disposition of different pendants molecules in a well define nanoparticle with a carbon core. This particular molecular shape allows the presentation of the chemical information encoded in a high number of potentially bioactive molecules. Therefore, the fullerene has been exploited for the multivalent presentation of glycans and other molecules that can interact with protein receptors that require a high number of ligands in close proximity. This multivalent binding strategy was successfully exploited in the past for the inhibition of the interaction and entry of viruses inside the host cells.

However, the complete functionalization of a fullerene scaffold with peptide units has not been achieved before. Now, scientists from the CIQUS in collaboration with researchers at the Universidad Complutense de Madrid have prepared, for the first time, a fully functionalized peptide fullerene hybrid that specifically recognizes the E-selectin protein receptor. The fullerene adduct molecule was prepared by using a dick-type chemical tool that allows the straightforward introduction of twelve peptide units around the fullerene in a quick an efficient manner. The peptide selected was a specific binder for the E-selectin and was synthesized at the CIQUS, in the group of Prof. Montenegro, by Iván Gallego Gómez who has been recently awarded with his Ph.D. title. This peptide was coupled to the fullerene hybrid in the group of Prof. Nazario Martín, in Universidad Complutense de Madrid, and the resulting hybrid was confirmed to multivalently bind to the E-selectin with high specificity.

This new study, recently published in Angewandte Chemie International Edition, also reports cell experiments that have confirmed that the fullerene peptide adduct can perfectly recognize and selectively penetrate into living cells that present the E-selectin receptor in their plasma membranes. The results reported showed the interesting properties and the future therapeutic potential of these new fully substituted peptide fullerene analogues for the recognition and potential functional modulation of protein receptors involved in cancer and tumor metastasis.

Reference

A 3D Peptide/[60]Fullerene Hybrid for Multivalent Recognition https://doi.org/10.1002/anie.202210043(link is external)