Marjolein M. E. Isendoorn, Giulia Castello, Çağla Koç, Nico Meeuwenoord, Jeroen D. C. Codée, Ferry Ossendorp, Dmitri V. Filippov
{"title":"单棕榈酰-N-烷基脲配体作为人类 Toll 样受体 2/6 异源二聚体的特异性激活剂。","authors":"Marjolein M. E. Isendoorn, Giulia Castello, Çağla Koç, Nico Meeuwenoord, Jeroen D. C. Codée, Ferry Ossendorp, Dmitri V. Filippov","doi":"10.1002/cbic.202400583","DOIUrl":null,"url":null,"abstract":"<p>Ligands for Toll-like-receptor 2 (TLR2) have demonstrated significant potential as immune-stimulating components in synthetic vaccines. Activation of TLR2 relies on the formation of dimeric complexes with either TLR1 or TLR6 and the nature of these dimers can impact therapeutic outcomes. The lipopeptide-based TLR2 ligands Pam<sub>3</sub>CysSK<sub>4</sub> and Pam<sub>2</sub>CysSK<sub>4</sub> have been extensively studied, and their recognition by different TLR-receptor heterodimers, TLR2/TLR1 and TLR2/TLR6, respectively, has been established. However, the high lipophilicity of these ligands, containing multiple palmitoyl residues, can result in solubility issues when used as vaccine adjuvants. To address this, we previously synthesized a less lipophilic ligand containing a single palmitoyl chain called mini-UPam, which effectively stimulates human moDC maturation. We here probe the receptor-dimer specificity of several mini-Upam derivatives and reveal that these mini-UPam are hTLR2/TLR6 selective ligands and that the introduction of longer urea alkyl chains does not shift the binding specificity to hTLR2/TLR1 heterodimers, in contrast to their Pam<sub>2</sub>CysSK<sub>4</sub> and Pam<sub>3</sub>CysSK<sub>4</sub> counterparts, pointing to a different binding mode of the UPam ligands.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":"25 23","pages":""},"PeriodicalIF":2.6000,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cbic.202400583","citationCount":"0","resultStr":"{\"title\":\"Mono-Palmitoyl-N-Alkylurea Ligands as Specific Activators of Human Toll-Like Receptor 2/6 Heterodimer\",\"authors\":\"Marjolein M. E. Isendoorn, Giulia Castello, Çağla Koç, Nico Meeuwenoord, Jeroen D. C. Codée, Ferry Ossendorp, Dmitri V. Filippov\",\"doi\":\"10.1002/cbic.202400583\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Ligands for Toll-like-receptor 2 (TLR2) have demonstrated significant potential as immune-stimulating components in synthetic vaccines. Activation of TLR2 relies on the formation of dimeric complexes with either TLR1 or TLR6 and the nature of these dimers can impact therapeutic outcomes. The lipopeptide-based TLR2 ligands Pam<sub>3</sub>CysSK<sub>4</sub> and Pam<sub>2</sub>CysSK<sub>4</sub> have been extensively studied, and their recognition by different TLR-receptor heterodimers, TLR2/TLR1 and TLR2/TLR6, respectively, has been established. However, the high lipophilicity of these ligands, containing multiple palmitoyl residues, can result in solubility issues when used as vaccine adjuvants. To address this, we previously synthesized a less lipophilic ligand containing a single palmitoyl chain called mini-UPam, which effectively stimulates human moDC maturation. We here probe the receptor-dimer specificity of several mini-Upam derivatives and reveal that these mini-UPam are hTLR2/TLR6 selective ligands and that the introduction of longer urea alkyl chains does not shift the binding specificity to hTLR2/TLR1 heterodimers, in contrast to their Pam<sub>2</sub>CysSK<sub>4</sub> and Pam<sub>3</sub>CysSK<sub>4</sub> counterparts, pointing to a different binding mode of the UPam ligands.</p>\",\"PeriodicalId\":140,\"journal\":{\"name\":\"ChemBioChem\",\"volume\":\"25 23\",\"pages\":\"\"},\"PeriodicalIF\":2.6000,\"publicationDate\":\"2024-10-09\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cbic.202400583\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ChemBioChem\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/cbic.202400583\",\"RegionNum\":4,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ChemBioChem","FirstCategoryId":"99","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/cbic.202400583","RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Mono-Palmitoyl-N-Alkylurea Ligands as Specific Activators of Human Toll-Like Receptor 2/6 Heterodimer
Ligands for Toll-like-receptor 2 (TLR2) have demonstrated significant potential as immune-stimulating components in synthetic vaccines. Activation of TLR2 relies on the formation of dimeric complexes with either TLR1 or TLR6 and the nature of these dimers can impact therapeutic outcomes. The lipopeptide-based TLR2 ligands Pam3CysSK4 and Pam2CysSK4 have been extensively studied, and their recognition by different TLR-receptor heterodimers, TLR2/TLR1 and TLR2/TLR6, respectively, has been established. However, the high lipophilicity of these ligands, containing multiple palmitoyl residues, can result in solubility issues when used as vaccine adjuvants. To address this, we previously synthesized a less lipophilic ligand containing a single palmitoyl chain called mini-UPam, which effectively stimulates human moDC maturation. We here probe the receptor-dimer specificity of several mini-Upam derivatives and reveal that these mini-UPam are hTLR2/TLR6 selective ligands and that the introduction of longer urea alkyl chains does not shift the binding specificity to hTLR2/TLR1 heterodimers, in contrast to their Pam2CysSK4 and Pam3CysSK4 counterparts, pointing to a different binding mode of the UPam ligands.
期刊介绍:
ChemBioChem (Impact Factor 2018: 2.641) publishes important breakthroughs across all areas at the interface of chemistry and biology, including the fields of chemical biology, bioorganic chemistry, bioinorganic chemistry, synthetic biology, biocatalysis, bionanotechnology, and biomaterials. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies, and supported by the Asian Chemical Editorial Society (ACES).