Site-specific effect of polar functional group-modification in lipids of TLR2 ligands for modulating the ligand immunostimulatory activity
[Display omitted] Toll-like receptor 2 (TLR2), a member of the TLR innate immune receptor family, recognizes lipoproteins from bacteria and modulates the immune response by inducing the expression of various cytokines. TLR2 has a large hydrophobic pocket that recognizes long fatty acyl groups on TLR...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2018-05, Vol.28 (9), p.1638-1641 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Arai, Yohei Inuki, Shinsuke Fujimoto, Yukari |
| description | [Display omitted]
Toll-like receptor 2 (TLR2), a member of the TLR innate immune receptor family, recognizes lipoproteins from bacteria and modulates the immune response by inducing the expression of various cytokines. TLR2 has a large hydrophobic pocket that recognizes long fatty acyl groups on TLR2 ligands. However, few studies have focused on the property of the hydrophobic TLR2 pocket. Based on the X-ray crystal structure of TLR2, small polar regions were found in the hydrophobic TLR2 pocket. Interactions between the polar residues and ligands were explored here by designing and synthesizing a Pam2CSK4 derivative of the TLR2 ligands, containing an amide group within the lipid moiety. We evaluated the binding affinities and immunomodulatory activities of these ligands. Results suggested that the amide groups in the lipid chain interacted with the polar residues in the hydrophobic lipid-binding pocket of TLR2. |
| doi_str_mv | 10.1016/j.bmcl.2018.03.042 |
| format | Article |
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Toll-like receptor 2 (TLR2), a member of the TLR innate immune receptor family, recognizes lipoproteins from bacteria and modulates the immune response by inducing the expression of various cytokines. TLR2 has a large hydrophobic pocket that recognizes long fatty acyl groups on TLR2 ligands. However, few studies have focused on the property of the hydrophobic TLR2 pocket. Based on the X-ray crystal structure of TLR2, small polar regions were found in the hydrophobic TLR2 pocket. Interactions between the polar residues and ligands were explored here by designing and synthesizing a Pam2CSK4 derivative of the TLR2 ligands, containing an amide group within the lipid moiety. We evaluated the binding affinities and immunomodulatory activities of these ligands. Results suggested that the amide groups in the lipid chain interacted with the polar residues in the hydrophobic lipid-binding pocket of TLR2.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2018.03.042</identifier><identifier>PMID: 29598910</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Adjuvants, Immunologic - chemical synthesis ; Adjuvants, Immunologic - chemistry ; Adjuvants, Immunologic - pharmacology ; Animals ; Cytokines - biosynthesis ; Dose-Response Relationship, Drug ; Humans ; Hydrophobic and Hydrophilic Interactions ; Ligands ; Lipids - chemical synthesis ; Lipids - chemistry ; Lipids - pharmacology ; Lipopeptide ; Macrophages - drug effects ; Macrophages - immunology ; Mice ; Molecular Structure ; Pam2CSK4 ; RAW 264.7 Cells ; Structure-Activity Relationship ; Toll-like receptor 2 ; Toll-Like Receptor 2 - antagonists & inhibitors ; Toll-Like Receptor 2 - immunology</subject><ispartof>Bioorganic & medicinal chemistry letters, 2018-05, Vol.28 (9), p.1638-1641</ispartof><rights>2018 Elsevier Ltd</rights><rights>Copyright © 2018 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c422t-55205bd66611d6fe22ca016af81b7e7198a54d779d80cdb29a194de5b2e5e4d03</citedby><cites>FETCH-LOGICAL-c422t-55205bd66611d6fe22ca016af81b7e7198a54d779d80cdb29a194de5b2e5e4d03</cites><orcidid>0000-0001-5320-3192</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X1830235X$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29598910$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Arai, Yohei</creatorcontrib><creatorcontrib>Inuki, Shinsuke</creatorcontrib><creatorcontrib>Fujimoto, Yukari</creatorcontrib><title>Site-specific effect of polar functional group-modification in lipids of TLR2 ligands for modulating the ligand immunostimulatory activity</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
Toll-like receptor 2 (TLR2), a member of the TLR innate immune receptor family, recognizes lipoproteins from bacteria and modulates the immune response by inducing the expression of various cytokines. TLR2 has a large hydrophobic pocket that recognizes long fatty acyl groups on TLR2 ligands. However, few studies have focused on the property of the hydrophobic TLR2 pocket. Based on the X-ray crystal structure of TLR2, small polar regions were found in the hydrophobic TLR2 pocket. Interactions between the polar residues and ligands were explored here by designing and synthesizing a Pam2CSK4 derivative of the TLR2 ligands, containing an amide group within the lipid moiety. We evaluated the binding affinities and immunomodulatory activities of these ligands. 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Toll-like receptor 2 (TLR2), a member of the TLR innate immune receptor family, recognizes lipoproteins from bacteria and modulates the immune response by inducing the expression of various cytokines. TLR2 has a large hydrophobic pocket that recognizes long fatty acyl groups on TLR2 ligands. However, few studies have focused on the property of the hydrophobic TLR2 pocket. Based on the X-ray crystal structure of TLR2, small polar regions were found in the hydrophobic TLR2 pocket. Interactions between the polar residues and ligands were explored here by designing and synthesizing a Pam2CSK4 derivative of the TLR2 ligands, containing an amide group within the lipid moiety. We evaluated the binding affinities and immunomodulatory activities of these ligands. Results suggested that the amide groups in the lipid chain interacted with the polar residues in the hydrophobic lipid-binding pocket of TLR2.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>29598910</pmid><doi>10.1016/j.bmcl.2018.03.042</doi><tpages>4</tpages><orcidid>https://orcid.org/0000-0001-5320-3192</orcidid></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry letters, 2018-05, Vol.28 (9), p.1638-1641 |
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| subjects | Adjuvants, Immunologic - chemical synthesis Adjuvants, Immunologic - chemistry Adjuvants, Immunologic - pharmacology Animals Cytokines - biosynthesis Dose-Response Relationship, Drug Humans Hydrophobic and Hydrophilic Interactions Ligands Lipids - chemical synthesis Lipids - chemistry Lipids - pharmacology Lipopeptide Macrophages - drug effects Macrophages - immunology Mice Molecular Structure Pam2CSK4 RAW 264.7 Cells Structure-Activity Relationship Toll-like receptor 2 Toll-Like Receptor 2 - antagonists & inhibitors Toll-Like Receptor 2 - immunology |
| title | Site-specific effect of polar functional group-modification in lipids of TLR2 ligands for modulating the ligand immunostimulatory activity |
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