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Nonpyrogenic Molecular Adjuvants Based on norAbu-Muramyldipeptide and norAbu-Glucosaminyl Muramyldipeptide: Synthesis, Molecular Mechanisms of Action, and Biological Activities in Vitro and in Vivo
R. Effenberg, P. Turánek Knötigová, D. Zyka, H. Čelechovská, J. Mašek, E. Bartheldyová, F. Hubatka, Š. Koudelka, R. Lukáč, A. Kovalová, D. Šaman, M. Křupka, L. Barkocziova, P. Kosztyu, M. Šebela, L. Drož, M. Hučko, M. Kanásová, AD. Miller, M....
Journal of medicinal chemistry.
2017 ;
60 (18) :
7745-7763.
[pub] 20170908
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články
Perzistentní odkaz
https://www.medvik.cz/link/bmc18016404
Grantová podpora
NV15-32198A
MZ0
CEP - Centrální evidence projektů
- MeSH
- acetylmuramyl-alanyl-isoglutamin analogy a deriváty chemie imunologie farmakologie MeSH
- adjuvancia imunologická chemie farmakologie MeSH
- antigeny povrchové chemie imunologie farmakologie MeSH
- bakteriální vakcíny chemie imunologie farmakologie MeSH
- Borrelia burgdorferi imunologie MeSH
- HEK293 buňky MeSH
- imunizace MeSH
- lidé MeSH
- lipoproteiny chemie imunologie farmakologie MeSH
- lymeská nemoc imunologie mikrobiologie MeSH
- myši inbrední BALB C MeSH
- myši MeSH
- protein NLRP3 agonisté imunologie MeSH
- proteiny vnější bakteriální membrány chemie imunologie farmakologie MeSH
- RAW 264.7 buňky MeSH
- tvorba protilátek MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články 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).
Citace poskytuje Crossref.org
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- $a Effenberg, Roman $u Department of Chemistry of Natural Compounds, University of Chemistry and Technology , Technická 5,166 28 Prague 6, Czech Republic.
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- $a 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).
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