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Ortho -Substituted lipidated Brartemicin derivative shows promising Mincle-mediated adjuvant activity

journal contribution
posted on 11.06.2020 by Amy Foster, Kristel Kodar, Mattheus Timmer, Bridget Stocker
This journal is © The Royal Society of Chemistry. The macrophage inducible C-type lectin (Mincle) is a pathogen recognition receptor (PRR) that is a promising target for the development of Th1-polarising vaccine adjuvants. We recently reported on the synthesis and evaluation of lipidated Brartemicin analogues that showed Mincle agonist activity, with our lead agonist exhibiting potent Th1 adjuvant activity that was greater than that of trehalose dibehenate (TDB). Herein, we report on the efficient synthesis and subsequent biological evaluation of additional lipidated Brartemicin analogues that were designed to determine the structural requirements for optimal Mincle signalling. While all the Brartemicin analogues retained their ability to signal through Mincle and induce a functional response, the o-substituted and m,m-disubstituted derivatives (5a and 5d, respectively) induced a potent inflammatory response when using cells of both murine and human origin, with this response being the greatest observed thus far. As the inflammatory response elicited by 5a was slightly better than that induced by 5d, our findings point to o-substituted Brartemicin analogues as the preferred scaffold for further adjuvant development.

History

Preferred citation

Foster, A.J., Kodar, K., Timmer, M.S. M. & Stocker, B.L. (2020). Ortho -Substituted lipidated Brartemicin derivative shows promising Mincle-mediated adjuvant activity. Organic and Biomolecular Chemistry, 18(6), 1095-1103. https://doi.org/10.1039/c9ob02397f

Journal title

Organic and Biomolecular Chemistry

Volume

18

Issue

6

Publication date

14/02/2020

Pagination

1095-1103

Publisher

Royal Society of Chemistry (RSC)

Publication status

Published

Online publication date

01/01/2020

ISSN

1477-0520

eISSN

1477-0539

Language

en

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