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Scientists Discover New Cyclization Reactions for Generating Macrocyclic Drug Leads

Scientists at EPFL have developed a brand new method to synthesize and show thousands of macrocyclic compounds, a family of chemical substances that are of great interest in the pharmaceutical trade. The research is published in Science Advances.

Macrocyclic compounds are ring-shaped molecules made by connecting two ends of linear molecules. One of their distinctive and exciting properties is that their cyclical configuration reduces their flexibility, which signifies that macrocycles want less power to fix targets than conventional small molecules.

Macrocycles show a remarkable ability to bind challenging targets that have flat, featureless surfaces. This has raised a tremendous curiosity in the pharmaceutical sector, which is especially interested in macrocyclic compounds with a molecular weight under 1 KDa, which might be small enough to pass the cell membrane and reach intracellular illness targets, e.g., proteins or even genes in the cell.

There aren’t enough appropriate macrocycle libraries or methods to produce such small macrocycles. The compound libraries that pharmaceutical companies use in the present day in high-throughput screens do contain 1-2 million different molecules; however, these are principally classical small molecules, and merely a handful are actual macrocyclic—at most, only a few hundred. That is too small a number for the screens to generate good hits when looking for possible drug candidates against challenging illness targets.

Now, scientists at EPFL have discovered a method to generate libraries of over 9,000 of macrocyclic molecules below 1 KDa, all with excessive structural diversity. “Initially, what we needed to do is generate orally obtainable or cell-permeable macrocyclic medicine,” says the research lead Professor Christian Heinis.

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