Custom Peptide Synthesis Services: New Methods for Macrocyclization of Peptides

Peptide macrocycles have been of growing interest over the past several years. With a need to stabilize scaffolds for proper orientation of key pharmacophore motifs for drug design efforts, methods that clearly allow for convenient and specific cyclization are widely desired in peptide labs around the world. To this end, the lab of Dr. Bradley Pentelute at MIT has recently described a method for cyclizing unprotected peptides through nitrogen arylation (DOI: 10.1021/jacs.6b03757). In this report, Lautrette, et al. show that peptidyl Lys amino side chains can be reacted with aromatic electrophiles such as dichloro or difluorbenzene via an SNAr reaction. The size of the ring can be tuned with different lengths of the amino acid side chain such as Orn, Dab or Dap. Reaction conditions were developed favoring an i+4 linkage in DMF as a solvent with a base such as Tris or DIEA at 37o C. Using optimized conditions, a P53 peptide inhibitor of M2D2 was constructed with a longer i+7 linkage and more a correspondingly longer perfluoroaromatic linker was developed which showed improved proteolytic stability as well as enhanced cellular permeability and nM inhibition.

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