4.8 Article

A Bionic-Homodimerization Strategy for Optimizing Modulators of Protein-Protein Interactions: From Statistical Mechanics Theory to Potential Clinical Translation

Journal

ADVANCED SCIENCE
Volume 9, Issue 11, Pages -

Publisher

WILEY
DOI: 10.1002/advs.202105179

Keywords

bionic-dimerization; nanomedicine; peptide; protein-protein interactions; statistical mechanics theory

Funding

  1. National Natural Science Foundation of China [22007076, 32171256, 12122210, 12072252]
  2. Thousand Talents Plan of Shaanxi Province
  3. The Young Talent Support Plan of Xi'an Jiaotong University

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This study introduces a new method to calculate the affinity of PPI modulators and significantly increases the affinity of PPI modulators through a simple homodimerization strategy.
Emerging protein-protein interaction (PPI) modulators have brought out exciting ability as therapeutics in human diseases, but its clinical translation has been greatly hampered by the limited affinity. Inspired by the homodimerize structure of antibody, the homodimerization contributes hugely to generating the optimized affinity is conjectured. Herein, a statistical-mechanics-theory-guided method is established to quantize the affinity of ligands with different topologies through analyzing the change of enthalpy and the loss of translational and rotational entropies. A peptide modulator for p53-MDM2 termed CPAP is used to homodimerize connecting, and this simple homodimerization can significantly increase the affinity. To realize the cellular internalization and tumor accumulation, (Dimer)CPAP and (Mono)CPAP are nanoengineered into gold(I)-CPAP supermolecule by the aurophilic interaction-driven self-assembly. Nano-(Dimer)CPAP potently suppressed tumor growth in lung cancer allograft model and a patient-derived xenograft model in more action than Nano-(Mono)CPAP, while keeping a favorable drug safety profile. This work not only presents a physico-mechanical method for calculating the affinity of PPI modulators, but also provides a simple yet robust homodimerization strategy to optimize the affinity of PPI modulators.

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