Synthetic TLR4-active glycolipids as vaccine adjuvants and stand-alone immunotherapeutics.
The design of vaccine adjuvants and stand-alone immunotherapeutics has historically been a mix of alchemy and accident partly because of the complex nature of the molecular mechanisms involved in immune system function. The recent discovery of pattern recognition receptors and toll-like receptors (TLRs) in particular on cells of the immune system has shown the important role that stimulation of these cell receptors by microbial products plays in both innate and adaptive immune responses. Considerable effort has been directed at developing pharmaceutically acceptable mimetics of many TLR-active natural products, including the main cell-surface component of Gram-negative bacteria: lipopolysaccharide (LPS). LPS and its active principle, lipid A, are potent stimulators of host defense systems via their interaction with TLR4. However, the profound pyrogenicity and lethal toxicity of LPS and lipid A have precluded their medicinal use. Structure/activity investigations on natural S. minnesota R595 lipid A and its derivatives have led to the development of a novel class of synthetic lipid A mimetics known as aminoalkyl glucosaminide phosphates (AGPs). This review discusses the evolution of the AGPs and related TLR4-active glycolipids with emphasis on structure/activity relationships in the AGP series and pre-clinical/clinical development of selected AGPs, including the potent vaccine adjuvant RC-529.
Johnson
David A
DA
GlaxoSmithKline Biologicals, 553 Old Corvallis Road, Hamilton, Montana 59840, USA. david.a.johnson@gskbio.com
D000276:Adjuvants, Immunologic / Q000138:chemical synthesis* / Q000494:pharmacology*; D002236:Carbohydrate Conformation; D006017:Glycolipids / Q000138:chemical synthesis* / Q000276:immunology / Q000494:pharmacology*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008050:Lipid A / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D051197:Toll-Like Receptor 4 / Q000187:drug effects* / Q000276:immunology
D000276:Adjuvants, Immunologic; D006017:Glycolipids; D008050:Lipid A; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4