Synthesis of Branched Trehalose Glycolipids and Their Mincle Agonist Activity

The Journal of Organic Chemistry
Jessie H BirdBridget L Stocker

Abstract

The macrophage inducible C-type lectin (Mincle) is a pattern recognition receptor that recognizes trehalose dimycolate (TDM), and trehalose dibehenate (TDB) and related trehalose diesters, and thus represents a promising target for the development of vaccine adjuvants based on the trehalose glycolipid scaffold. To this end, we report on the synthesis of a series of long-chain α-branched, β-modified trehalose monoesters and diesters to explore how glycolipid structure affects signaling through Mincle. Key steps in our synthetic strategy include a Fráter-Seebach α-alkylation to install the C20 aliphatic lipid on a malic acid derivative, and the formation of a β,γ-epoxide as an intermediate from which modifications to the β-position of the lipid can be made. Biological evaluation of the derivatives using nuclear factor of activated T cells (NFAT)-green fluorescent protein (GFP) reporter cell lines expressing mMincle or hMincle revealed that the hMincle agonist activity of all diesters was superior to that of the current lead trehalose glycolipid adjuvant TDB, while the activity of several monoesters was similar to that of their diester counterparts for mMincle, but all showed reduced hMincle agonist activity. Taken together, diest...Continue Reading

References

Feb 1, 1991·Proceedings of the National Academy of Sciences of the United States of America·B J SpargoJ H Crowe
Apr 5, 2002·Chemistry : a European Journal·Peter WipfSeiji Yoshimura
Jan 28, 2005·Angewandte Chemie·K C NicolaouBrian S Safina
Sep 9, 2008·Nature Immunology·Sho YamasakiTakashi Saito
Jul 8, 2009·Organic & Biomolecular Chemistry·Ramón BadorreyJosé A Gálvez
Dec 17, 2009·The Journal of Experimental Medicine·Eri IshikawaSho Yamasaki
Feb 19, 2010·The Journal of Immunology : Official Journal of the American Association of Immunologists·Hanne SchoenenRoland Lang
Oct 13, 2011·Chembiochem : a European Journal of Chemical Biology·Ashna A KhanBridget L Stocker
Apr 11, 2012·Carbohydrate Research·Ashna A KhanMattie S M Timmer
Jun 5, 2012·Progress in Lipid Research·Jan A VerschoorJohan Grooten
May 1, 2013·The Journal of Immunology : Official Journal of the American Association of Immunologists·Kevin ShenderovAlan Sher
Aug 21, 2013·The Journal of Biological Chemistry·Hadar FeinbergKurt Drickamer
Oct 9, 2013·Proceedings of the National Academy of Sciences of the United States of America·Atsushi FurukawaKatsumi Maenaka
Jan 18, 2014·Chembiochem : a European Journal of Chemical Biology·Bridget L StockerMattie S M Timmer
Apr 16, 2014·The Journal of Biological Chemistry·Yuki HattoriMasahiko Sugita
Feb 26, 2015·Chemical Communications : Chem Comm·Phillip L van der PeetSpencer J Williams
Apr 18, 2015·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Neela D S RambaruthKurt Drickamer
Jul 24, 2015·The Journal of Immunology : Official Journal of the American Association of Immunologists·Jenny OstropRoland Lang
Feb 23, 2017·Proceedings of the National Academy of Sciences of the United States of America·Alexiane DecoutJérôme Nigou
Dec 13, 2017·Frontiers in Immunology·Spencer J Williams
Jan 2, 2018·Journal of Medicinal Chemistry·Amy J FosterBridget L Stocker
Feb 2, 2018·Frontiers in Immunology·Chriselle D BraganzaBridget L Stocker

❮ Previous
Next ❯

Citations

Nov 28, 2019·Organic & Biomolecular Chemistry·Ayesha KhanBridget L Stocker
Dec 24, 2019·Organic & Biomolecular Chemistry·Amy J FosterBridget L Stocker
Mar 3, 2020·Organic & Biomolecular Chemistry·Santanu Jana, Suvarn S Kulkarni
Mar 18, 2020·Chemical Communications : Chem Comm·Dylan G M SmithSpencer J Williams
Aug 31, 2019·Current Opinion in Chemical Biology·Joscha MeiersAlexander Titz
Mar 23, 2021·The FEBS Journal·Marko AnderluhSandra J van Vliet

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.