A Multifaceted Secondary Structure Mimic Based On Piperidine‐piperidinones

Abstract

Minimalist secondary structure mimics are typically made to resemble one interface in a protein-protein interaction (PPI), and thus perturb it. We recently proposed suitable chemotypes can be matched with interface regions directly, without regard for secondary structures. Here we describe a modular synthesis of a new chemotype 1, simulation of its solution-state conformational ensemble, and correlation of that with ideal secondary structures and real interface regions in PPIs. Scaffold 1 presents amino acid side-chains that are quite separated from each other, in orientations that closely resemble ideal sheet or helical structures, similar non-ideal structures at PPI interfaces, and regions of other PPI interfaces where the mimic conformation does not resemble any secondary structure. 68 different PPIs where conformations of 1 matched well were identified. A new method is also presented to determine the relevance of a minimalist mimic crystal structure to its solution conformations. Thus dld-1 faf crystallized in a conformation that is estimated to be 0.91 kcal mol À1 above the minimum energy solution state.

Application of C-Terminal 7-Azabicyclo[2.2.1]heptane to Stabilize β-Strand-like Extended Conformation of a Neighboring α-Amino Acid

“…Many examples of the former approach have been reported using various nonamino acid units such as dibenzofurans, 6,7 oligoureas, 8−10 metallopeptides, 11−16 indolin-3-ones, 17 imidazolidin-2-ones, 18 epiindolines, 19 and oligothienylpyridines. 20 These mimics do not contain interstrand hydrogen bonding sites. Therefore, their general applicability to mimic protein−protein interactions via β-sheet formation is unclear.…”

Foldamers in Medicinal Chemistry

“…Later they designed benzoylurea oligomers (3) as an alternative to oligophenylenes to mimic up to eight turns of an α-helix, and to solve synthesis as well as water solubility issues when extended scaffolds are needed. [64] Other groups have also developed efficient non-helical mimetics of biologically active α-helices, based on aromatic backbones (such as oligo-benzamides, [65] pyridazines, [66] -pyridyles [67] or -piperidine-piperidinones [68] ). Arora et al, on the other hand, have reported the oligooxopiperazine scaffold as chiral nonaromatic topographical helix mimetic.…”

Construction of diverse peptide structural architectures via chemoselective peptide ligation

“…19,20 Other examples include peptides targeting HIV integrase, BCl-2 and β-catenin. [21][22][23] Apart from the stapling chemistry, some other motifs have been explored, including the β-strands mimetics 24 and loops motif 25 that display more complex topologies. Examples of tertiary mimetics as PPI inhibitors has also been reported, including α-and α/β-peptides derived from the "Z-domain" scaffold.…”