Highly Preorganized Calixarene Tweezers for Protein Recognition.

Area of Science:

• Supramolecular Chemistry
• Medicinal Chemistry
• Enzyme Inhibition

Background:

• Calixarene scaffolds provide structural stability and tunable geometry for designing selective supramolecular inhibitors.
• Taspase 1 is a cancer-related protease involved in cellular processes.

Purpose of the Study:

• To develop and synthesize a focused library of preorganized multivalent calix[4]arene tweezers targeting Taspase 1.
• To investigate the impact of linker rigidity, functionalization, and multivalency on Taspase 1 inhibition.

Main Methods:

• Synthesis of seven cone-conformation calix[4]arene derivatives.
• Meta-dynamics simulations to assess linker flexibility and preorganization.
• Biochemical binding assays to evaluate enzyme inhibition and binding affinity.

Main Results:

• Rigid linkers, particularly benzyl linkers, promoted structural preorganization of calixarene tweezers.
• Bivalent and upper-rim derivatives (c2Tl, uc2T, uc4T) most effectively disrupted the Taspase 1/Importin α-interaction.
• Inhibition potency was enhanced by increased multivalency and linker rigidity, with low micromolar K_D values observed for c2Tl and uc4T.

Conclusions:

• Rigid, preorganized calix[4]arene ligands are effective scaffolds for targeted Taspase 1 inhibition.
• The design of calixarene tweezers can be optimized by controlling linker rigidity and multivalency for enhanced enzyme inhibition.
• These findings establish a promising strategy for developing novel enzyme inhibitors for cancer therapy.