New pharmaceutical compounds to treat serious diseases

Scientists from the Ecole Polytechnique Fédéralede Lausanne (EPFL), the University of Padova and the Ca' Foscari Department of Molecular Sciences and Nanosystems have made a very significant discovery in the field of pharmaceuticals, developing a new way of rapidly producing and isolating thousands of macrocyclic compounds, a family of molecules that are of great interest to the pharmaceutical industry. The study was published by the prestigious journal Science Advances..

The interest for this type of molecule derives from the fact that numerous drugs, such as the immunosuppressive cyclosporine, the antibiotic vancomycin and the anti-cancer drug dactinomycin, are all macrocyclic compounds. These molecules, which until now were produced using natural compounds, can now be synthesized quickly and in large numbers, using robotic platforms.

Macrocyclic compounds are ring shaped and are prepared by means of the cyclization of open-chain molecules. These compounds possess numerous qualities that are of particular interest to the pharmaceutical industry. For example, they have a low molecular weight, which allows them to pass through the cell membrane and reach targets inside the cell, whether these be proteins or genes. Furthermore, their compact and rigid structure means that the functional groups of these molecules can position themselves in multiple areas within the space, giving them greater binding affinity with the target protein.

In other words, they manage to remain bound to the target protein for longer, meaning that less active ingredient is required to achieve the desired effect, offering greater effectiveness. The greater the affinity between the macrocyclic compound and its target, the greater its therapeutic power and the lower the dose that needs to be administered to the patient, thus making it safer and less expensive to use.

However, up until now, there was always a hurdle to overcome: there were no effective methodologies that allowed these molecules to be generated in large numbers. The collections of compounds that pharmaceutical companies currently use contain roughly 1-2 million different molecules, of which only a handful, or at the most one hundred or so, are actual macrocyclic compounds. This was a restriction because such a small number of compounds made it impossible to identify potential therapeutic agents to treat serious diseases.

Now, researchers from EPFL, the University of Padova and Ca’ Foscari University of Venice have developed a new method for generating rapidly libraries of around 10,000 macrocyclic compounds (100 times higher) with low molecular weight. (<1 kDa) and high structural diversity. "Initially, we wanted to create new drugs that could be administered orally and that were permeable to cells," explained Professor Christian Heinis of the Ecole Polytechnique Fédéralede Lausanne (EPFL), whose laboratory led the research. These collections of molecules were developed by "cyclizing" short linear peptides. The yields of the cyclization reactions proved to be so efficient that they did not need to undergo subsequent purification. The screening performed using these macrocyclic compounds identified inhibitors for multiple proteins, including thrombin, an important target for coagulation disorders.

"We have made a fundamental contribution towards understanding how these new macrocyclic compounds bind with the target protein," explains Alessandro Angelini, researcher at the Department of Molecular Sciences and Nanosystems at Ca’ Foscari University of Venice and member of the European Centre for Living Technology (ECLT). Structural X-ray analysis of the compound bound to thrombin showed that these molecules are capable of inducing the formation of new binding sites to which they can adhere perfectly. The excellent adhesion of the inhibitor to its target could not have been predicted using computational methods, giving further value to the qualities of these collections of macrocyclic compounds."

The next step for the researchers is to generate macrocyclic compounds that are able to break protein-protein interactions within a diseased cell, for which no effective therapeutic agents currently exist. This will have very important areas of application in the treatment of serious diseases, such as cancer.