Immunoactive peptides, FK-156 and FK-565. I. Enhancement of host resistance to microbial infection in mice.

Abstract

The protective effect of an immunoactive peptide, D-lactoyl-L-alanyl-r-D-glutamyl-(L)meso-diaminopimelyl-(L)-glycine (FK-156) and a related compound, heptanoyl-r-D-glutamyl-(L)meso-diaminopimelyl-(D)-alanine (FK-565) was determined in mice with various kinds of microbial infections. FK-156 and FK-565 were given to mice either subcutaneously or orally before challenge. The drugs enhanced significantly the defense of mice against acute systemic infections induced by various extracellular and facultative intracellular organisms, and subcutaneous abscess by Staphylococcus aureus. The protective effect of these drugs against Escherichia coli infection differed considerably depending on the route of administration; FK-156 was only effective by the parenteral route; however, FK-565 was effective by both parenteral and oral routes. After subcutaneous dosing with FK-156, the enhancement of host defense of mice against E. coli infection was more rapid than against Listeria infection. The enhancing effects of FK-156 and FK-565 on host defense of mice against pseudomonal infection was more potent than other immunoactive drugs.

Nucleotide-Binding Oligomerization Domain 1 Mediates Recognition of Clostridium difficile and Induces Neutrophil Recruitment and Protection against the Pathogen

“…Because Nod1 stimulation is also protective against several types of bacteria (17,(27)(28)(29)(30) and prestimulation by synthetic Nod1-stimulating compounds before infection confers resistance against multiple pathogens (33), it will be interesting to test whether local administration of Nod1 agonists such as KF1B will be beneficial in the prevention or treatment of C. difficile-induced pseudomembranous colitis. Nod1 stimulation is known to predominantly stimulate nonimmune cells that lack the ability to secrete potentially harmful cytokines such as TNF and IL-1, which is consistent with the observation that Nod1 stimulants induce chemokines and antimicrobial proteins without causing severe inflammation (10).…”

Nod1 Ligands Induce Site-Specific Vascular Inflammation

“…Severe combined immunodeficiency (SCID) mice developed weaker but significant arteritis, suggesting a partial involvement of acquired immunity in the inflammation induced by a pure Nod1 ligand, whereas no arteritis was observed in Nod1-knockout mice (Supplemental Table IB and Figure 2B). As FK565 is highly stable and effective by parenteral and oral routes, 16 FK565 was orally administered (Supplemental Table IC). All BALB/c mice showed coronary arteritis/valvulitis after oral administration of 6 days (100 g/day) per week of FK565 with LPS priming, and the severity of coronary arteritis/valvulitis increased with the duration of the administration.…”

“…On the basis of the fact that a Nod1 agonist, FK565, is very stable against temperature and acid, 16 coronary arteritis was successfully induced by oral administration of FK565. This is the first coronary arteritis animal model induced by oral administration of a pure synthetic Nod1 ligand.…”

The stimulatory effect of a muscle protein hydrolysate from Atlantic cod,Gadus morhuaL., on Atlantic salmon,Salmo salarL., head kidney leucocytes

“…A more penetrating study will be performed to characterize the active component of the peptide fraction. Another peptide, FK-565 (heptanoyl-y-Dglutamyl-(L)-meso-diaminopimelyl-(D)-alanine) has been shown to be active against microbial infection in mice (Mine et al, 1983a;1983b). Kitao & Yoshida (1986) found that the FK-565 peptide induced protection against intraperitoneal Aeromonas salmonicida infection in rainbow trout.…”