Lipidated Brartemicin Analogues Are Potent Th1-Stimulating Vaccine Adjuvants

Journal of Medicinal Chemistry
Amy J FosterBridget L Stocker

Abstract

Effective Th1-stimulating vaccine adjuvants typically activate antigen presenting cells (APCs) through pattern recognition receptors (PRRs). Macrophage inducible C-type lectin (Mincle) is a PRR expressed on APCs and has been identified as a target for Th1-stimulating adjuvants. Herein, we report on the synthesis and adjuvanticity of rationally designed brartemicin analogues containing long-chain lipids and demonstrate that they are potent Mincle agonists that activate APCs to produce inflammatory cytokines in a Mincle-dependent fashion. Mincle binding, however, does not directly correlate to a functional immune response. Mutation studies indicated that the aromatic residue of lead compound 9a has an important interaction with Mincle Arg183. In vivo assessment of 9a highlighted the capability of this analogue to augment the Th1 response to a model vaccine antigen. Taken together, our results show that lipophilic brartemicin analogues are potent Mincle agonists and that 9a has superior in vivo adjuvant activity compared to TDB.

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Citations

Feb 2, 2018·Frontiers in Immunology·Chriselle D BraganzaBridget L Stocker
Nov 28, 2019·Organic & Biomolecular Chemistry·Ayesha KhanBridget L Stocker
Dec 24, 2019·Organic & Biomolecular Chemistry·Amy J FosterBridget L Stocker
Mar 18, 2020·Chemical Communications : Chem Comm·Dylan G M SmithSpencer J Williams
Aug 28, 2020·Frontiers in Bioengineering and Biotechnology·Junqing WangJinjun Shi
Mar 23, 2021·The FEBS Journal·Marko AnderluhSandra J van Vliet
Sep 12, 2020·Chemical Reviews·Wen-Hao Li, Yan-Mei Li
May 22, 2018·The Journal of Organic Chemistry·Jessie H BirdBridget L Stocker
Dec 7, 2019·Journal of Medicinal Chemistry·Kendal T RyterJay T Evans

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