Image: Schematic of the protein-protein interaction
The discovery signified a major step towards the development of targeted, light-controlled drugs, whose effects would be limited to a specific area and time, reducing side effects.
Now, in recent experiments, the same researchers have been using their photo-sensitive molecules to control clathrin-mediated endocytosis, a process whereby cells absorb certain substances that they need to function properly. In doing so, they’ve made a discovery that greatly expands the field of potential inhibitors, as it questions the need for one of the previously supposed design requisites of these molecules.
“As many protein-protein interactions are mediated by short, often helical, linear peptides (small proteins), we thought our photoswitchable molecules had to be designed to mimic these rigid peptides in order to be able inhibit the PPI,” explains Pau Gorostiza of IBEC’s Nanoprobes and Nanoswitches group. “In fact, we found that they don’t need to have the same rigid structure, and that flexible structures actually show a greater inhibitory capacity, as well as better photoswitching ability.”
The absence of a rigid, helical structure, therefore, is not a limitation when selecting candidates for photoswitchable inhibitors of PPIs, meaning that when developing further potential inhibitors, researchers can look to the wide group of more flexible peptides for their candidates.
“These results are another step forward a general approach to photocontrol therapeutically relevant intracellular protein-protein interactions,” says Ernest Giralt, leader the Peptides and Proteins group at IRB Barcelona. “The behavior showed by these peptides highlights the advantage that can proceed from the partial flexibility of some protein-protein interaction inhibitors, which allows the binder to structurally ‘adapt’ to the target protein,” adds Laura Nevola, co-first author of the paper at IRB Barcelona.
The most immediate therapeutic applications expected for photoswitchable inhibitors is for diseases affecting superficial tissue such as the skin, retina and external mucus membranes. In the future, photo-sensitive molecules could be used to study, for example, in vitro endocytosis in cancer cells – where this process is uncontrolled – which would allow selective inhibition of the cells’ proliferation.
Another area of application would be in developmental biology, where cells require endocytosis to change shape and function. Their development also opens up entire new fields of research, such as optopharmacology and optogenetics.
André Martin-Quiro, Laura Nevola, Kay Eckelt, Sergio Madurga, Pau Gorostiza and Ernest Giralt (2015). “Absence of a Stable Secondary Structure is not a Limitation for Photoswitchable Inhibitors of b-Arrestin/b-Adaptin 2 Protein-Protein Interaction”
. Chemistry & Biology