Circling back to basics
Macrocycles have been a hot topic for chemists and pharmacologists alike for the promise they hold of reaching druggable targets that small molecules cannot. Although they are still much more challenging than small molecules to develop, a trio of studies might offer a way forward by proposing new design guidelines,1 identifying protein-protein interfaces to target2 and providing a new method to synthesize cyclic peptides (see Box 1, "Cyclotide synthesis").3
The papers were published in Nature Chemical Biology alongside an editorial call to action for research to support macrocycle discovery and development.4The proposals echoed those discussed by academic and industry leaders at SciBX's 2012 Summit on Innovation in Macrocycle Drug Discovery.5
"Developing macrocycles is a three-component problem-what do you want to target, how do you design a macrocycle to target it and which method can you use for synthesis?" asked Adrian Whitty, an associate professor of chemistry at Boston University. "This whole field is at an intersection of what you would like to make, what you are able to make and what you can target. Each of those three areas has been gradually pushed forward, and in sum we are in a much better position than we were five years ago. No solution to any two of those problems can be effective without the third, and now I see all three of those areas pushing forward rapidly."