Structure–Activity Relationships in Toll-Like Receptor 2-Agonists Leading to Simplified Monoacyl Lipopeptides
| Autor: | Tyler C. Lewis, Rajalakshmi Balakrishna, Hemamali J. Warshakoon, Geetanjali Agnihotri, Breanna M. Crall, Timothy P. Day, Subbalakshmi S. Malladi, Sunil A. David |
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| Rok vydání: | 2011 |
| Předmět: |
Models
Molecular Steric effects Stereochemistry Stereoisomerism Crystal structure Article Lipopeptides Mice Structure-Activity Relationship chemistry.chemical_compound Adjuvants Immunologic Thioether Drug Discovery Animals Humans Structure–activity relationship Molecule Molecular Structure Chemistry alpha-Linolenic Acid Lipopeptide Toll-Like Receptor 2 Linoleic Acids Solubility Molecular Medicine Acyl group |
| Zdroj: | Journal of Medicinal Chemistry. 54:8148-8160 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm201071e |
| Popis: | Toll-like receptor 2-agonistic lipopeptides typified by S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-R-cysteinyl-S-serine (PAM(2)CS) compounds are potential vaccine adjuvants. In continuation of previously reported structure-activity relationships on this chemotype, we have determined that at least one acyl group of optimal length (C(16)) and an appropriately oriented ester carbonyl group is essential for TLR2-agonistic activity. The spacing between one of the palmitoyl ester carbonyl and the thioether is crucial to allow for an important H-bond, which observed in the crystal structure of the lipopeptide:TLR2 complex; consequently, activity is lost in homologated compounds. Penicillamine-derived analogues are also inactive, likely due to unfavorable steric interactions with the carbonyl of Ser 12 in TLR2. The thioether in this chemotype can be replaced with a selenoether. Importantly, the thioglycerol motif can be dispensed with altogether and can be replaced with a thioethanol bridge. These results have led to a structurally simpler, synthetically more accessible, and water-soluble analogue possessing strong TLR2-agonistic activities in human blood. |
| Databáze: | OpenAIRE |
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