Researchers have devised a way to use isonitrile chemistry to constrain peptides reversibly, making them water soluble and easier to work with in syntheses (J. Am. Chem. Soc., DOI: 10.1021/ja2023898). The constraint, a dimethyleneoxy group that creates a seven-membered ring that includes nitrogens on two adjacent amino acids, causes the peptides to bend, permitting the two ends to fold together. The folding satisfies the peptides’ hydrophobic needs, thus making them soluble in water and discouraging them from forming aggregates with other peptide molecules. The constraint can then be released chemically, causing the peptides to unfold into their usual water-insoluble and aggregation-prone selves. Xiangyang Wu, Peter K. Park, and Samuel J. Danishefsky of Sloan-Kettering Institute for Cancer Research install the dimethyleneoxy constraints by using an isonitrile and carboxylic acid reaction developed earlier by Danishefsky’s group. The tendency of peptides and proteins to form aggregates not only leads to conditions like Alzheimer’s disease but also makes them hard to manage synthetically. The new approach “points to a direction that could help solve that problem” for synthetic chemists, Danishefsky says.