Development of actin dimerization inducers inspired by actin-depolymerizing macrolides

Area of Science:

• Medicinal Chemistry
• Molecular Pharmacology
• Biochemistry

Background:

• Natural cytotoxic compounds like swinholide A and rhizopodin inhibit actin dynamics by sequestering actin dimers.
• Actin dynamics are crucial for cellular processes, and their dysregulation is implicated in cancer.
• Antitumor macrolide aplyronine A possesses actin-binding side chains that can be modified.

Purpose of the Study:

• To develop novel protein-protein interaction (PPI) modulators based on aplyronine A.
• To synthesize structurally simplified actin-binding side-chain dimers of aplyronine A.
• To investigate the effect of these analogs on actin polymerization and structure.

Main Methods:

• Chemical synthesis of aplyronine A analogs with a fixed C4 linker.
• Assessment of filamentous actin depolymerization.
• Cross-linking experiments to detect actin dimer formation.
• Molecular dynamics simulations to analyze structural changes in actin complexes.

Main Results:

• The C4 linker analog demonstrated more potent depolymerization of filamentous actin compared to natural aplyronines.
• Cross-linking confirmed the formation of actin dimers upon treatment with the C4 linker analog.
• Molecular dynamics simulations revealed a distorted and twisted orientation of actin dimers induced by the analog, distinct from rhizopodin.

Conclusions:

• Structurally simplified aplyronine A analogs can potently inhibit actin dynamics by forming actin dimers.
• The C4 linker analog represents a promising lead for developing new anticancer drugs targeting cytoskeletal dynamics.
• This study highlights the potential of PPI modulators in drug discovery for cancer and other diseases.