“Stapled” peptides are typically designed to replace two non-interacting residues with a constraining, olefinic staple. To mimic interacting leucine and isoleucine residues, we have created new amino acids that incorporate a methyl in the γ-position of the stapling amino acid S5. We have incorporated them into a sequence derived from steroid receptor coactivator 2, which interacts with estrogen receptor α. The best peptide (IC50 = 89 nM) replaces isoleucine 689 with an S-γ-methyl stapled amino acid, and has significantly higher affinity than unsubstituted peptides (390 and 760 nM). Through x-ray crystallography and molecular dynamics studies, we show that the conformation taken up by the S-γ-methyl peptide minimizes syn-pentane interactions between α- and γ-methyl groups.

Nrf2 is the major transcription factor that regulates many of the cytoprotective enzymes involved in the adaptive stress response. Modulation of Nrf2 could be therapeutically useful in a number of disease states. Activation can occur through either an electrophilic or non-electrophilic mechanism. To date, most of the research has focused on electrophilic Nrf2 activators, but there is increasing interest in non-electrophilic modulators of Nrf2. This Digest examines the current selection of small molecules that modulate Nrf2 through non-electrophilic mechanisms, and it highlights new opportunities for this important therapeutic target.

A new computational approach to obtain quantitative energy profiles for helix folding was used in the design of orthogonal hydrocarbon and lactam bicyclic peptides. The proteolytically stable, "cross-stitched" peptide SRC2-BCP1 shows nanomolar affinity for estrogen receptor α and X-ray crystallography confirms a helical binding pose.

Given the ubiquity of the ⍺-helix in the proteome, there has been much research in developing mimics of ⍺-helices, and most of this study has been toward developing proteinprotein interaction inhibitors. A common strategy for mimicking ⍺-helices has been through the use of constrained, helical peptides. The addition of a constraint typically provides for conformational and proteolytic stability and, in some cases, cell permeability. Some of the most well-known strategies included are lactam formation and hydrocarbon "stapling." Beyond those strategies, there have been many recent advances in developing constrained peptides. The purpose of this review is to highlight recent advances in the development of new helix-stabilizing technologies, constraint diversification strategies, tether diversification strategies, and combination strategies that create new bicyclic helical peptides. K E Y W O R D S alpha helix, helical peptides, peptide chemistry, protein-protein interactions 1 | INTRODUCTIONThere are a multitude of protein-protein interactions in the cell that are mediated by ⍺-helices, and in many disease states it would be advantageous to mimic features of an ⍺-helix with a small molecule or peptide. A common strategy for mimicking ⍺-helices has been through the use of constrained, helical peptides. 1-9 Doing so provides for conformational stability by reducing the number of degrees of freedom of the peptide and/or by facilitating ⍺-helical hydrogen bonding. This strategy also often provides for proteolytic stability: many proteases recognize an extended peptide conformation, but because of the conformational rigidity imparted by the constraint, helical peptides are not readily recognized by proteases that otherwise might recognize an Med Res Rev. 2019;39:749-770.wileyonlinelibrary.com/journal/med