Structure-activity relationship of lipopeptide Group A streptococcus (GAS) vaccine candidates on toll-like receptor 2.
Incorporation of lipoamino acids (LAAs) into peptide structures effectively imparts self-adjuvanting activity onto otherwise ineffective immunogens. Our fully synthetic lipopeptide vaccine candidates against group A streptococcus (GAS) were composed of J14 as a target GAS B-cell epitope alongside a universal helper T-cell epitope (P25) and a LAA-based lipid moiety. In the current study, we investigated the ability of our lipopeptides to activate nuclear factor-kappaB (NF-kappaB) in a toll-like receptor-2 (TLR2)-dependent manner as the possible mode of action and reported the structure-function requirements for novel TLR2 targeting lipopeptides based on LAAs. The NF-kappaB activation was dependent on the dose and the length of the alkyl chains of the incorporated lipid moieties with the hierarchy LAA 3 (16 carbons)>LAA 2 (14 carbons)>LAA 1 (12 carbons). The position of the lipid moiety (C-terminus vs. N(epsilon)-terminus of the central lysine residue) does not significantly affect NF-kappaB activation. Lipopeptides containing different copies of LAA 3 were synthesized and the di-lipidated analogue was the most effective in NFkappaB activation.
Zaman
Mehfuz
M
The University of Queensland, School of Chemistry and Molecular Biosciences (SCMB), St. Lucia 4072, Queensland, Australia.
Abdel-Aal
Abu-Baker M
AM
The University of Queensland, School of Chemistry and Molecular Biosciences (SCMB), St. Lucia 4072, Queensland, Australia.
Phillipps
Karen S M
KSM
The University of Queensland, School of Chemistry and Molecular Biosciences (SCMB), St. Lucia 4072, Queensland, Australia.
Fujita
Yoshio
Y
The University of Queensland, School of Chemistry and Molecular Biosciences (SCMB), St. Lucia 4072, Queensland, Australia.
Good
M F
MF
The Queensland Institute of Medical Research (QIMR), Brisbane 4029, Queensland, Australia.
Toth
Istvan
I
The University of Queensland, School of Chemistry and Molecular Biosciences (SCMB), St. Lucia 4072, Queensland, Australia. Electronic address: i.toth@uq.edu.au.
D000942:Antigens, Bacterial / Q000276:immunology*; D002460:Cell Line; D000090266:Chromobox Protein Homolog 5; D018985:Epitopes, B-Lymphocyte / Q000235:genetics / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D017930:Genes, Reporter; D006801:Humans; D055666:Lipopeptides / Q000276:immunology*; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000276:immunology; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology; D022541:Streptococcal Vaccines / Q000276:immunology*; D013297:Streptococcus pyogenes / Q000276:immunology*; D013329:Structure-Activity Relationship; D051195:Toll-Like Receptor 2 / Q000276:immunology*
D000942:Antigens, Bacterial; C000715594:CBX5 protein, human; D018985:Epitopes, B-Lymphocyte; D018984:Epitopes, T-Lymphocyte; D055666:Lipopeptides; D016328:NF-kappa B; D011994:Recombinant Proteins; D022541:Streptococcal Vaccines; D051195:Toll-Like Receptor 2; D000090266:Chromobox Protein Homolog 5; D008156:Luciferases