Chemical Nanoengineering Advance in Designing Light-Controlled Drugs

Spanish researchers have been able to design photo-switchable molecules to control protein-protein interactions in a remote and noninvasive way. These applications will serve as a prototype to develop photo-switchable drugs, whose effects would be targeted to a given body region and time, thereby reducing the side effects on other regions.

The study is a result of the European project OpticalBullet, funded by the European Research Council (ERC; Brussels, Belgium). The scientific cooperation between biotechnologists, chemists, and physicists from various Catalan institutes, headed by Dr. Pau Gorostiza, from the Institute for Bioengineering of Catalonia (IBEC; Spain), and Dr. Ernest Giralt, from the Institute for Research in Biomedicine (IRB; Barcelona; Spain), has led to a breakthrough that will help in the development of light-regulated therapeutic molecules. The project was published online June 18, 2013, in the journal Angewandte Chemie.

The design, synthesis and structure of peptides and proteins lab is headed by Dr. Giralt, also senior professor at the University of Barcelona and holder of the 2011 Spanish National Research Prize, has synthesized two peptides, which upon irradiation with light change shape, thereby allowing or preventing a specific protein-protein interaction. The association of these two proteins is required for endocytosis, a process by which cells allow molecules to cross the cell membrane and enter. The Italian scientist Laura Nevola, a postdoctoral researcher who works in Dr. Giralt’s lab, and Andrés Martín-Quirós, a PhD student with Dr. Gorostiza’s lab, coauthors of the study, have spent four years working on the design of photosensitive peptides.

“Photosensitive peptides act like traffic lights and can be made to give a green or red light for cell endocytosis. They are powerful tools for cell biology,” explained Dr. Giralt. “These molecules allow us to use focalized light like a magic wand to control biological processes and to study them,” added the physicist Dr. Gorostiza, ICREA professor, and head of the nanoprobes and nanoswitches lab at IBEC.

The researchers highlight the immediate applicability of these molecules to study, for example, in vitro endocytosis in cancer cells, where this process is uncontrolled, would allow selective inhibition of the proliferation of these cells. Moreover, they would also allow the study of developmental biology, where cells require endocytosis to change shape and function, processes that are orchestrated with great spatial and temporal precision. In this context, photosensitive peptides will allow the manipulation of the complex development of a multicellular organism by means of light patterns. “In view of the results, we are now working towards a general recipe to design photo-switchable inhibitory peptides that can be used to manipulate other protein-protein interactions inside cells by applying light,” clarified the researchers.

“This first breakthrough will allow us to generate the same kind of peptides for chemical-medical applications,” said Dr. Giralt. Dr. Gorostiza was the individual who came up with the notion of engineering biologic and pharmacologic processes through the use of light after spending five years specializing in this field at the University of California in Berkeley. The coordinator of the ERC Starting Grant project OpticalBullet and of the ERC proof of concept Theralight, both involving collaboration with Dr. Giralt’s lab, stated that, “the most immediate therapeutic applications we can expect is for diseases affecting superficial tissue such as the skin, the retina and the most external mucosal membranes.”

The modification of biologic processes by utilizing light is leading to the development of cutting-edge tools for biology and medicine and opening up new research fields, such as optopharmacology and optogenetics. The combination of drugs with external devices to control light may contribute to the development of personalized medicine in which treatments can be adapted to each patient, limiting the time given regions are treated, thus markedly reducing unwanted effects.

To work towards the development of photosensitive drugs, scientists must enhance the photochemical response of the compounds and be able to stimulate them at visible wavelengths. “Prolonged illumination with ultraviolet light is toxic for cells and is therefore a clear limitation as well has having little tissue penetration capacity,” Dr. Giralt explained as an example. Furthermore, the photoconversion of the compounds needs to be improved as does their stability in the dark in order to be able to “on demand, design them in such a way that they relax rapidly when irradiation with light stops or that they “remember” for hours or days the light stimulation received,” added Dr. Gorostiza.

This study has also involved the collaboration of researchers with IRB Barcelona’s Advanced Digital Microscopy Platform, who designed an adhoc program to be able to qualitatively and quantitatively confirm the effects of the peptides inside the cells in real time. Similarly, in the field of biology, the team has been supported by Dr. Artur Llobet’s group at Institut d'Investigació Biomèdica de Bellvitge (IDIBELL; Catalonia, Spain).

Related Links:
Institute for Bioengineering of Catalonia
Institute for Research in Biomedicine
Institut d'Investigació Biomèdica de Bellvitge