Chemical structure and biological activity relationship of bacterial cell walls and muramyl peptides.
The biological activities of the cell walls of bacteria having different types of peptidoglycans, and those of stereoisomers and analogs of muramyl dipeptide (MDP), of N-acetylglucosaminyl-beta(1-4)-N-acetylmuramyl tetrapeptides having different L- and D-amino acids at the COOH-terminus, and of 6-O-acyl-MDPs were examined to elucidate the relationship between structure and activity. Replacement of the L-alanine residue of MDP with glycine and replacement of the D-isoglutamine residue with L-isoglutamine, L-glutamic acid, and D-isoasparagine, but not with D-glutamic acid, caused a marked decrease in the biological activities of the MDP molecule. Test disaccharide tetrapeptides, irrespective of the configuration of COOH-terminal amino acid, showed strong immunoadjuvant activity and stimulation of macrophages, whereas those having COOH-terminal L-amino acids exhibited greater pyrogenicity, induction of acute joint inflammation, and hemorrhagic necrosis at a primed site than those having COOH-terminal D-amino acids. Introduction of an alpha-branched higher fatty acid to the muramic acid residue resulted in the disappearance of pyrogenicity after i.v. injection, an increase of adjuvanticity, and a loss of dependence on administration vehicles. The lack of the immunopotentiating activity (adjuvanticity) in cell walls from group B-type bacterial species was explained by the combined inhibitory effects of the replacement of the L-alanine residue by glycine and involvement of the alpha-carboxyl group of the D-glutamic acid residue in linking with neighboring peptide subunits.
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001419:Bacteria / Q000032:analysis*; D002473:Cell Wall / Q000032:analysis*; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D011749:Pyrogens; D013045:Species Specificity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D011749:Pyrogens; D000119:Acetylmuramyl-Alanyl-Isoglutamine