Helix stabilizing cyclic peptides with mixed stereochemistry as anti-cancer drugs

DIPC Seminars

Speaker

Julen Aduriz
DIPC

When

2026/02/06
10:00

Place

Faculty of Chemistry Auditorium

Host

David De Sancho

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Protein–protein interactions are central to cellular function, and many involve intrinsically disordered proteins or regions that adopt α-helical structure upon binding to folded domains. These interactions are frequently implicated in disease but remain challenging drug targets due to the large, extended interfaces formed by multiple turns of an α-helix. One prominent example is the anti-apoptotic protein Mcl-1, which suppresses programmed cell death by binding pro-apoptotic partners such as Bid (BH3-interacting domain death agonist). Its overexpression in cancer contributes to therapy resistance. Helix-stabilized peptides incorporating macrocyclic constraints have emerged as promising inhibitors of such interactions. In this work, we combine molecular dynamics simulations and quantum mechanical calculations to examine how N-terminal macrocyclization reshapes the conformational landscape and binding properties of intrinsically disordered peptides. We quantify the impact of cyclization on α-helical propensity, validate our results against experimental data, and analyze the stereochemical, electronic, and entropic factors underlying helix stabilization and enhanced binding affinity.