Development of actin dimerization inducers inspired by actin-depolymerizing macrolides
Several natural cytotoxic C 2 -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 d...
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| Veröffentlicht in: | Chemical communications (Cambridge, England) England), 2024-05, Vol.6 (37), p.491-4913 |
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| creator | Itakura, Moeka Utomo, Didik Huswo Kita, Masaki |
| description | Several natural cytotoxic
C
2
-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. |
| doi_str_mv | 10.1039/d4cc01304b |
| format | Article |
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C
2
-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.</description><identifier>ISSN: 1359-7345</identifier><identifier>EISSN: 1364-548X</identifier><identifier>DOI: 10.1039/d4cc01304b</identifier><identifier>PMID: 38623638</identifier><language>eng</language><publisher>England: Royal Society of Chemistry</publisher><subject>Actin Depolymerizing Factors - chemistry ; Actin Depolymerizing Factors - pharmacology ; Actins - chemistry ; Actins - metabolism ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Chains ; Depolymerization ; Dimerization ; Dimers ; Lactones ; Macrolides - chemical synthesis ; Macrolides - chemistry ; Macrolides - pharmacology ; Modulators ; Molecular dynamics ; Molecular Dynamics Simulation ; Protein Multimerization - drug effects ; Proteins</subject><ispartof>Chemical communications (Cambridge, England), 2024-05, Vol.6 (37), p.491-4913</ispartof><rights>Copyright Royal Society of Chemistry 2024</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c332t-cc16ebb9c868be93d2e9a8ee9d5bf85d869cd67a8da7e9806a25df5cce7db4503</cites><orcidid>0000-0001-6685-4461</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38623638$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Itakura, Moeka</creatorcontrib><creatorcontrib>Utomo, Didik Huswo</creatorcontrib><creatorcontrib>Kita, Masaki</creatorcontrib><title>Development of actin dimerization inducers inspired by actin-depolymerizing macrolides</title><title>Chemical communications (Cambridge, England)</title><addtitle>Chem Commun (Camb)</addtitle><description>Several natural cytotoxic
C
2
-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.</description><subject>Actin Depolymerizing Factors - chemistry</subject><subject>Actin Depolymerizing Factors - pharmacology</subject><subject>Actins - chemistry</subject><subject>Actins - metabolism</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Chains</subject><subject>Depolymerization</subject><subject>Dimerization</subject><subject>Dimers</subject><subject>Lactones</subject><subject>Macrolides - chemical synthesis</subject><subject>Macrolides - chemistry</subject><subject>Macrolides - pharmacology</subject><subject>Modulators</subject><subject>Molecular dynamics</subject><subject>Molecular Dynamics Simulation</subject><subject>Protein Multimerization - drug effects</subject><subject>Proteins</subject><issn>1359-7345</issn><issn>1364-548X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpd0U1LxDAQBuAgiruuXrwrBS8iVNMmaZOjdv2CBS8q3kqaTCVLv0xaYf31ZrergrlkYB6GzBuEjiN8GWEirjRVCkcE02IHTSOS0JBR_ra7rpkIU0LZBB04t8T-RIzvownhSUwSwqfodQ6fULVdDU0ftGUgVW-aQJsarPmSvWmbwDR6UGCdL1xnLOigWI0u1NC11WpjTfMe1FLZtjIa3CHaK2Xl4Gh7z9DL3e1z9hAunu4fs-tFqAiJ-1CpKIGiEIonvABBdAxCcgChWVFypnkilE5SybVMQXCcyJjpkikFqS4ow2SGzse5nW0_BnB9XhunoKpkA-3gcuLz4Zimft0ZOvtHl-1gG_86r6hIacwY8-piVH4T5yyUeWdNLe0qj3C-Tjuf0yzbpH3j8el25FDUoH_pT7wenIzAOvXb_fsu8g0PuoXW</recordid><startdate>20240502</startdate><enddate>20240502</enddate><creator>Itakura, Moeka</creator><creator>Utomo, Didik Huswo</creator><creator>Kita, Masaki</creator><general>Royal Society of Chemistry</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7SR</scope><scope>7U5</scope><scope>8BQ</scope><scope>8FD</scope><scope>JG9</scope><scope>L7M</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-6685-4461</orcidid></search><sort><creationdate>20240502</creationdate><title>Development of actin dimerization inducers inspired by actin-depolymerizing macrolides</title><author>Itakura, Moeka ; 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C
2
-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.</abstract><cop>England</cop><pub>Royal Society of Chemistry</pub><pmid>38623638</pmid><doi>10.1039/d4cc01304b</doi><tpages>4</tpages><orcidid>https://orcid.org/0000-0001-6685-4461</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Chemical communications (Cambridge, England), 2024-05, Vol.6 (37), p.491-4913 |
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| language | eng |
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| source | MEDLINE; Royal Society Of Chemistry Journals; Alma/SFX Local Collection |
| subjects | Actin Depolymerizing Factors - chemistry Actin Depolymerizing Factors - pharmacology Actins - chemistry Actins - metabolism Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Chains Depolymerization Dimerization Dimers Lactones Macrolides - chemical synthesis Macrolides - chemistry Macrolides - pharmacology Modulators Molecular dynamics Molecular Dynamics Simulation Protein Multimerization - drug effects Proteins |
| title | Development of actin dimerization inducers inspired by actin-depolymerizing macrolides |
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