Helicity Synchronization-Induced Kinetic Stabilization against Helix Inversion in Stapled Peptides: Effects of 3₁₀/α Block Sequence and Double-Stapling Topology

Herein, we report a series of nonoverlapping doubly stapled block-type peptides composed entirely of achiral components and containing α-α, 3₁₀-3₁₀, α-3₁₀, and 3₁₀-α helical architectures. Despite their distinct geometries and hydrogen-bonding patterns, neighboring helical segments were found to communicate efficiently, resulting in exclusive formation of homochiral (<i>P</i>,<i>P</i>)- and (<i>M</i>,<i>M</i>)-helices.

Reversing the order of the α- and 3₁₀-helical blocks produced a 5.5-fold difference in helix inversion rate, demonstrating that block sequence controls <i>P</i>/<i>M</i> interconversion kinetics. The nonoverlapping α-α architecture underwent <i>P</i>/<i>M</i> interconversion approximately 1600 times faster than the previously reported overlapping doubly stapled analogue, in which the staples partially overlap within a single helical domain, underscoring the importance of double-stapling topology.