Immunobiological activities of synthetic lipid A analogs and related compounds as compared with those of bacterial lipopolysaccharide, re-glycolipid, lipid A, and muramyl dipeptide

Abstract

Thirteen acylated and phosphorylated derivatives of 0-1,6-linked glucosamine disaccharide (lipid A analogs), which were synthesized after the structural model of Salmonella-type lipid A, and seven similar derivatives of glucosamine monosaccharide (lipid A-related compounds) were studied for their immunobiological activities. These included mitogenicity and polyclonal B cell activation enhancement of migration of monocytes and polymorphonuclear leukocytes derived from human peripheral blood, stimulation of guinea pig peritoneal macrophages, activation of human complement, and stimulation of serum antibody production and induction of delayed-type hypersensitivity against ovalbumin in guinea pigs. Comparisons were made with lipid A, Re-glycolipid, lipopolysaccharide of natural sources, and a well-known synthetic adjuvant, N-acetylmuramyl-L-alanyl-Disoglutamine. Some of the lipid A analogs were found to manifest the mitogenic, polyclonal B cell-activating macrophage-stimulating, complement-activating, and immunostimulating activities, although the observed activities were generally far less than those of natural products in intensity and efficiency. Other immunobiological effects exhibited by most of the synthetic lipid A analogs were the enhancement of migration of monocytes and polymorphonuclear leukocytes. It is premature to draw definite conclusions on structure-activity relationships, since a few compounds which were active in some assay systems were scarcely active in other assays. However, an indisputable fact was that P-1,6-glucosamine disaccharide la,4'-diphosphate, which carries two amide-bound (R)-3-hydroxytetradecanoyl and three ester-bound tetradecanoyl residues, and thus has the structure most closely resembling natural lipid A among test compounds in this study, was definitely active in all of the present assay systems. However, its potency was generally much less than natural products. Some of glucosamine monosaccharide derivatives, especially N-(R)-3-[(R)-3-hydroxytetradecanoyloxy]tetradecanoyI glucosamine, also exerted all of the in vitro activities described above. This fact suggests that a glucosamine disaccharide structure may not necessarily be a prerequisite as far as the in vitro immunobiological activities tested are concerned.

Immunobiological activities of a porin fraction isolated from Fusobacterium nucleatum ATCC 10953

“…The porin fraction significantly enhanced the migration of human peripheral blood monocytes (Fig. 10) under assay conditions in which the reference LPS was found inactive, in accordance with our previous finding (15).…”

Immunopharmacological activities of a synthetic counterpart of a biosynthetic lipid A precursor molecule and of its analogs

“…as the main test organism by Westphal et al (30) and the structure of lipid A of Escherichia coli heptoseless mutant proposed by Rosner et al (22)(23)(24), as provisional target structural models (15). Contrary to expectation, the immunopharmacological activities of these synthetic preparations were far less than those of natural products (lipid A and lipopolysaccharide [LPS]), although some compounds exhibited detectable activities in some assay systems (13). Similar findings have been obtained by other investigators (14,18,28,29) with the notable exception of Yasuda et al (31,32), who have reported definite biological activities of the analogs incorporated in artificial membrane vesicles.…”

“…The assay for enhanced migration of human polymorphonuclear leukocytes (PMNL) was performed with a multiwell chemotaxis assembly (Neuro Probe, Cabin John, Md.) (13). Determination was made of the number of PMNL which migrated to the surface of the membrane sheet adjacent to the lower well with an added test specimen in triplicate for each experimental point.…”

Chemotaxis of human monocytes by synthetic peptides that mimic segments of Porphyromonas gingivalis fimbrial protein

“…On the other hand, P. gingivalis LPS mainly induced chemokinesis, and the LPS was also found to exhibit chemotactic activity of monocytes under the same conditions described above ( Table 2). This is in contrast to the previous results that LPS prepared from Salmonella enteritidis, Escherichia coli and Pseudomonas aeruginosa induced no significant migration of monocytes, while their lipid A stimulated human monocyte migration, which was mainly due to chemokinesis under the same conditions described above (6). Thus, it is of interest to know how P. gingivalis LPS enhances the migration of monocytes.…”