Topologically Tunable α‐Helix Mimetics for Targeting Protein–Protein Interactions
Abstract
Abstract A novel strategy to replicate diverse α‐helical conformations found at the interfaces of protein–protein interactions is developed with a topologically tunable biphenyl scaffold. A set of N,N’‐diphenyl‐4,4′‐biphenyldicarboxamide scaffolds were designed as customizable α‐helix mimetics, capable of reproducing a wide range of helical surfaces that may be difficult to be replicated with previously reported α‐helix mimetics. These scaffolds were evaluated for their capability to mimic the α‐helical BH3 domains of Bcl‐2 family proteins. By modifying the substituents and their positions, both pan‐active and selective inhibitors of anti‐apoptotic Bcl‐2 family members were developed, each exhibiting distinct binding profiles. This unique approach offers a powerful tool for mimicking naturally occurring α‐helices and distinguishing subtle differences in bound conformations with target proteins.
Article Details
Authors (5)
Tae‐Kyung Lee
Department of Chemistry and Biochemistry University of Texas at Dallas Richardson TX 75080 USA
Luxi Chen
Chia‐Yuan Chen
Department of Chemistry and Biochemistry University of Texas at Dallas Richardson TX 75080 USA
Henry Neal
Department of Chemistry and Biochemistry University of Texas at Dallas Richardson TX 75080 USA
Jung‐Mo Ahn
Department of Chemistry and Biochemistry University of Texas at Dallas Richardson TX 75080 USA