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Development of actin dimerization inducers inspired by actin-depolymerizing macrolides
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DOI：10.1039/d4cc01304b.png)
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Several natural cytotoxic C2-symmetric bis-lactones, such as swinholide A and rhizopodin, sequester actin dimer from the actin network and potently inhibit actin dynamics. To develop new protein-protein interaction (PPI) modulators, we synthesized structurally simplified actin-binding side-chain dimers of antitumor macrolide aplyronine A. By fixing the two side-chains closer than those of rhizopodin, the C4 linker analog depolymerized filamentous actin more potently than natural aplyronines. Cross-link experiments revealed that actin dimer was formed by treatment with the C4 linker analog. Molecular dynamics simulations showed that this analog significantly changed the interaction and spatial arrangement of the two actins compared to those in rhizopodin to provide a highly distorted and twisted orientation in the complex. Our study may promote the development of PPI-based anticancer and other drug leads related to cytoskeletal dynamics. A side-chain dimer analog of aplyronine A potently depolymerized filamentous actin, and gave a highly distorted and twisted orientation of actin in a 2 : 1 complex.
Keyword:
POTENT ANTITUMOR SUBSTANCE
MARINE NATURAL-PRODUCTS
PROTEIN-PROTEIN INTERACTION
APLYRONINE-A
DIMERIC MACROLIDES
BINDING MACROLIDE
SWINHOLIDE-A
RHIZOPODIN
CONGENERS
CYTOSKELETON
期刊
IF:
4.2
论文数:
5.9W
被引数:
16.5W
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引用论文
Marine natural products that interfere with multiple cytoskeletal protein interactions.png)
NATURAL PRODUCT REPORTS
NATURAL PRODUCT REPORTSIF10.6
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分享收藏Synthesis and Biological Activities of Aplyronine A Analogues toward the Development of Antitumor Protein-Protein Interaction Inducers between Actin and Tubulin: Conjugation of the C1-C9 Macrolactone Part and the C24-C34 Side ChainACS OMEGA
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ACS OMEGAIF4.3
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