Journal of Medicinal Chemistry p. 7745 - 7763 (2017)
Update date:2022-08-15
Topics:
Effenberg, Roman
Turánek Kn?tigová, Pavlína
Zyka, Daniel
?elechovská, Hana
Ma?ek, Josef
Bartheldyová, Eli?ka
Hubatka, Franti?ek
Koudelka, ?těpán
Luká?, Róbert
Kovalová, Anna
?aman, David
K?upka, Michal
Barkocziova, Lucia
Kosztyu, Petr
?ebela, Marek
Dro?, Ladislav
Hu?ko, Michal
Kanásová, Mária
Miller, Andrew D.
Ra?ka, Milan
Ledvina, Miroslav
Turánek, Jaroslav
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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