title: Structural requirements of muramylpeptides for induction of necrosis at sites primed with Mycobacterium tuberculosis in guinea pigs.
abstract: Intracutaneous injection of N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP) in guinea pigs caused an extensive necrotic reaction in footpads prepared by injection of heat-killed Mycobacterium tuberculosis in water-in-mineral-oil emulsion. We examined a variety of analogs and derivatives of muramylpeptides for their ability to provoke this reaction. A maximum and a minimum structure responsible for the necrotic reaction were found to be N-acetylglycosaminyl-beta(1-4)-N-acetylmuramyl-tripeptide (GlcNAc-MurNAc-L-Ala-D-isoGln-meso-A2pm) and MDP, respectively. An unexpected finding was that GlcNAc-MurNAc-tetrapeptides having L-amino acids at their C termini, unlike comparable compounds having C-terminal D-amino acids, exhibited definite necrosis-inducing activity, probably due to their tendency to undergo in vivo degradation to GlcNAc-MurNAc-tripeptide. Introduction of some acyl groups, especially the stearoyl group, to the 6-O position of the muramic acid or the peptide moiety of muramylpeptides increased the necrosis-inducing activity of the parent molecules. However, this was not observed with 1-thio-muramic acid analogs of MDP. Modification of the alpha- or gamma-carboxyl groups of the glutamic acid residues of muramylpeptides tended to decrease their necrosis-inducing ability. Analogs and derivatives of muramylpeptides which are capable of inducing necrosis at a primed site, with few exceptions, exhibited powerful adjuvanticity against ovalbumin in guinea pigs. However, the reverse was not necessarily true.
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000031:analogs & derivatives* / Q000276:immunology / Q000633:toxicity*; D000276:Adjuvants, Immunologic; D000818:Animals; D005260:Female; D006168:Guinea Pigs; D009169:Mycobacterium tuberculosis / Q000276:immunology; D009336:Necrosis / Q000209:etiology*; D013329:Structure-Activity Relationship
chemical_list: D000276:Adjuvants, Immunologic; D000119:Acetylmuramyl-Alanyl-Isoglutamine