Novel Synthesis Method Generates Macrocycle Molecules With High Structural Diversity

Pharmaceutical scientists are interested in macrocyclic compounds with a molecular weight below 1 KDa—small enough to cross the cell membrane and reach intracellular disease targets, e.g., proteins or even genes in the cell.

The challenge is that there are not enough suitable macrocycle libraries or methods to generate such small macrocycles. Compound libraries used by pharmaceutical companies in high-throughput screens contain 1–2 million different molecules, but those are mostly classical small molecules. Only a handful are actual macrocyclics, and not enough for the screens to yield good hits when searching for possible drug candidates against challenging disease targets.

Ecole Polytechnique Fédérale de Lausanne researchers have found a way to generate libraries of more than 9,000 macrocyclic molecules below 1 KDa, all with high structural diversity.

The libraries were generated by “cyclizing” short linear peptides in combination with diverse linker reagents, which promote chemical bonding. Yields of the macrocyclization reactions turned out to be so efficient that there was no need for purification. Importantly, the new method also led to the discovery of surprisingly efficient macrocyclization reactions based on the ligation of thiol and amino groups of short peptides.

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