Pseudoprolines as stereoelectronically tunable proline isosteres

The cyclic structure of proline (Pro) confers unique conformational properties on this natural amino acid that influences polypeptide structure and function. Pseudoprolines are a family of Pro isosteres that incorporate a heteroatom, most prominently oxygen or sulfur but also silicon and selenium, to replace the Cβ or Cγ carbon atom of the pyrrolidine ring. These readily synthetically accessible structural motifs can facilitate facile molecular editing in a fashion that allows modulation of the amide bond topology of dipeptide elements and influence over ring pucker. While the properties of pseudoprolines have been exploited most prominently in the design of oligopeptide analogues, they have potential application in the design and optimization of small molecules. In this Digest, we summarize the physicochemical properties of pseudoprolines and illustrate their potential in drug discovery by surveying examples of applications in the design of bioactive molecules.