Scientists at the Federal Institute of Technology Lausanne (EPFL) have successfully generated more than 9,000 of macrocyclic molecules under 1 KDa, with high structural diversity. The libraries were generated through ‘cyclizing’ of short linear peptides along with different linker reagents that supplement chemical bonding. The macrocyclization reactions were extremely efficient, and there was no need for purification. The new method, which was already a key breakthrough in the field, also helped the researchers learn of the macrocyclization reactions based on ligation of thiol as well as amino groups of short peptides.
Macrocyclic compounds are molecules that have a ring shape and are made by connecting the two ends of linear molecules. They have unique properties, such as their cyclical configuration reduces their flexibility, which indicates that macrocycles require less energy to bind targets compared to conventional small molecules. Macrocycles possess the ability to bind difficult targets that have flat, featureless surfaces. This has raised a lot of interest in the pharmaceutical industry that is especially interested in the compounds, with a molecular weight under 1 KDa, which might be able to reach intracellular disease targets like proteins or genes in the cell. The compound libraries used by pharmaceutical companies in high-throughput screens contain 1-2 million diverse molecules, but these molecules are mostly classical small molecules, and only some are actual macrocyclic molecules. Thus, it becomes challenging for the screens to obtain good hits when looking for potential drug candidates against specific disease targets.
The research was supported by EPFL’s Biomolecular Screening Facility (BSF). Gerardo Turcatti, Head, BSF, has commented that EPFL has formulated the liquid handling processes for the combinational synthesis and for screening macrocyclic compound libraries. The screening was able to identify binders of several disease targets, along with inhibitors of thrombin, which is a crucial target of coagulation disorders. In an X-ray structure analysis of a thrombin inhibitor, a macrocycle was seen attached to its target.