A study led by CiQUS researchers highlighted by the editors of Communications Chemistry

Controlling oncogenic KRAS signaling pathways with a Palladium-responsive peptide(link is external), an article published last year in Communications Chemistry by CiQUS researchers, has been recently featured in the renowned open access journal from Nature Portfolio for chemical sciences. The editorial board members of Communications Chemistry have selected the work led by Prof. Eugenio Vázquez and Prof. José Luis Mascareñas into their 2022 content highlights, remarking the advances it represents for the area of constrained peptides. The editors celebrate this "interdisciplinary manuscript at the interface of chemical biology and supramolecular chemistry", underlining the broad range of experiments used and the important concepts introduced.

α-helices are one of the fundamental building blocks of proteins and also a key player in the language that proteins use to communicate. Thus, α-helices have become a hot target for the development of new protein-protein interaction inhibitors. However, developing such α-helix inhibitors (known as α-helix peptidomimetics) is not easy because α-helices are delicate structures that tend to unfold. The typical approach involves the syntheis of analogs with some sort of structural tether that maximizes the α-helical structure. "Going beyond the classic metal-stabilized α-helices [...] we hypothesized that metal chelation could be applied for the development of switchable α-helical peptides that modify their folding and binding affinity in response to an external stimulus, namely, the presence of a Pd(II)" explains CiQUS principal investigator Prof. Eugenio Vázquez.

The authors applied this new concept for the development of peptidomimetics targeting KRAS, which is one of the major oncogenes and is responsible of up to 30% of all cancers, including 95% of pancreatic, 45% of colorectal cancers and 33% of lung adenocarcinomas. They demonstrated that these Pd(II)-peptidomimetics could modulate the activity of KRAS in living cells, which suggests new opportunities in basic research and therapeutic applications arising from this new strategy.

According to the authors, this is the first demonstration of a designed metallopeptide that can modulate a signaling pathway in living cells. This approach uncovers "new possibilities for the design of dynamic α-helix peptidomimetics that exploit the folding-upon-binding mechanism and can be extended to other biological targets".