Nonpyrogenic Molecular Adjuvants Based on norAbu-Muramyldipeptide and norAbu-Glucosaminyl Muramyldipeptide: Synthesis, Molecular Mechanisms of Action, and Biological Activities in Vitro and in Vivo
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
- MeSH
- Acetylmuramyl-Alanyl-Isoglutamine analogs & derivatives chemistry immunology pharmacology MeSH
- Adjuvants, Immunologic chemistry pharmacology MeSH
- Antigens, Surface chemistry immunology pharmacology MeSH
- Bacterial Vaccines chemistry immunology pharmacology MeSH
- Borrelia burgdorferi immunology MeSH
- HEK293 Cells MeSH
- Immunization MeSH
- Humans MeSH
- Lipoproteins chemistry immunology pharmacology MeSH
- Lyme Disease immunology microbiology MeSH
- Mice, Inbred BALB C MeSH
- Mice MeSH
- NLR Family, Pyrin Domain-Containing 3 Protein agonists immunology MeSH
- Bacterial Outer Membrane Proteins chemistry immunology pharmacology MeSH
- RAW 264.7 Cells MeSH
- Antibody Formation MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Acetylmuramyl-Alanyl-Isoglutamine MeSH
- Adjuvants, Immunologic MeSH
- Antigens, Surface MeSH
- Bacterial Vaccines MeSH
- glucosaminylmuramyl-2-alanine-D-isoglutamine MeSH Browser
- Lipoproteins MeSH
- OspA protein MeSH Browser
- NLR Family, Pyrin Domain-Containing 3 Protein MeSH
- Bacterial Outer Membrane Proteins MeSH
Fatty acyl analogues of muramyldipeptide (MDP) (abbreviated N-L18 norAbuGMDP, N-B30 norAbuGMDP, norAbuMDP-Lys(L18), norAbuMDP-Lys(B30), norAbuGMDP-Lys(L18), norAbuGMDP-Lys(B30), B30 norAbuMDP, L18 norAbuMDP) are designed and synthesized comprising the normuramyl-l-α-aminobutanoyl (norAbu) structural moiety. All new analogues show depressed pyrogenicity in both free (micellar) state and in liposomal formulations when tested in rabbits in vivo (sc and iv application). New analogues are also shown to be selective activators of NOD2 and NLRP3 (inflammasome) in vitro but not NOD1. Potencies of NOD2 and NLRP3 stimulation are found comparable with free MDP and other positive controls. Analogues are also demonstrated to be effective in stimulating cellular proliferation when the sera from mice are injected sc with individual liposome-loaded analogues, causing proliferation of bone marrow-derived GM-progenitors cells. Importantly, vaccination nanoparticles prepared from metallochelation liposomes, His-tagged antigen rOspA from Borrelia burgdorferi, and lipophilic analogue norAbuMDP-Lys(B30) as adjuvant, are shown to provoke OspA-specific antibody responses with a strong Th1-bias (dominance of IgG2a response). In contrast, the adjuvant effects of Alum or parent MDP show a strong Th2-bias (dominance of IgG1 response).
APIGENEX s r o Poděbradská 173 5 Prague 9 190 00 Czech Republic
Institute of Pharmaceutical Science King's College London London SE1 9NH United Kingdom
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