Glucose monomycolates based on single synthetic mycolic acids

Sahb, Mohaned M.; Dulayymi, Juma’a R. Al; Baird, Mark S.

doi:10.1016/j.chemphyslip.2015.06.005

Cited by 8 publications

(10 citation statements)

References 41 publications

(38 reference statements)

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“…Among the mycobacterial MA-containing glycolipids tested, and in sharp contrast with data reported by Ishikawa et al (7), glucose monomycolate (GlcMM) was the most stimulatory, with EC 50 values even lower than those determined for TDM (∼0.5 log lower) (18,19) (Figs. 1 B and C and SI Appendix, Fig. S2).…”

Section: Resultscontrasting

confidence: 53%

Rational design of adjuvants targeting the C-type lectin Mincle

Decout

Silva‐Gomes

Drocourt

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

134

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The advances in subunit vaccines development have intensified the search for potent adjuvants, particularly adjuvants inducing cellmediated immune responses. Identification of the C-type lectin Mincle as one of the receptors underlying the remarkable immunogenicity of the mycobacterial cell wall, via recognition of trehalose-6,6′-dimycolate (TDM), has opened avenues for the rational design of such molecules. Using a combination of chemical synthesis, biological evaluation, molecular dynamics simulations, and protein mutagenesis, we gained insight into the molecular bases of glycolipid recognition by Mincle. Unexpectedly, the fine structure of the fatty acids was found to play a key role in the binding of a glycolipid to the carbohydrate recognition domain of the lectin. Glucose and mannose esterified at O-6 by a synthetic α-ramified 32-carbon fatty acid showed agonist activity similar to that of TDM, despite their much simpler structure. Moreover, they were seen to stimulate proinflammatory cytokine production in primary human and murine cells in a Mincle-dependent fashion. Finally, they were found to induce strong Th1 and Th17 immune responses in vivo in immunization experiments in mice and conferred protection in a murine model of Mycobacterium tuberculosis infection. Here we describe the rational development of new molecules with powerful adjuvant properties. mycobacteria | glycolipid | innate immunity

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Section: Resultscontrasting

confidence: 53%

Rational design of adjuvants targeting the C-type lectin Mincle

Decout

Silva‐Gomes

Drocourt

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

134

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“…Mycolic Acid preparation and formulation MA and their sugar esters were prepared as described previously (32,(49)(50)(51)(52)(53)(54). Table S1 provides structural information.…”

Section: Immunohistochemistrymentioning

confidence: 99%

CD1b-restricted GEM T cell responses are modulated byMycobacterium tuberculosismycolic acid meromycolate chains

Chancellor

Tocheva

Cave-Ayland

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Tuberculosis, caused by Mycobacterium tuberculosis, remains a major human pandemic. Germline-encoded mycolyl lipid-reactive (GEM) T cells are donor-unrestricted and recognize CD1b-presented mycobacterial mycolates. However, the molecular requirements governing mycolate antigenicity for the GEM T cell receptor (TCR) remain poorly understood. Here, we demonstrate CD1b expression in tuberculosis granulomas and reveal a central role for meromycolate chains in influencing GEM-TCR activity. Meromycolate fine structure influences T cell responses in TB-exposed individuals, and meromycolate alterations modulate functional responses by GEM-TCRs. Computational simulations suggest that meromycolate chain dynamics regulate mycolate head group movement, thereby modulating GEM-TCR activity. Our findings have significant implications for the design of future vaccines that target GEM T cells. Mycobaterium tuberculosis | GEM T cells | CD1b | Mycolate lipids |

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“…Stocks of synthetic glycolipids (synthetized at Bangor University [25][26][27][28]30,31], TDB (Invivogen) and natural TDM from Mtb (Adipogen) were solubilised in chloroform-methanol solution (9:1) at 5mg/mL. The different glycolipids were then dissolved in isopropanol and coated on flat bottomed culture plates (Greiner).…”

Section: Preparation Of Glycolipid Coated Platesmentioning

confidence: 99%

“…To address the relationship between the structure and the inflammatory power of mycolate esters and the signalling pathways involved, we have assayed in this study thirty-eight single synthetic mycolate ester isomers of high purity and known stereochemistry [25][26][27][28]. The mycolate esters tested here vary in terms of their carbohydrate moiety (trehalose, glucose or arabinose) and in terms of the number, nature and class of mycolic acids bound to it.…”

mentioning

confidence: 99%

Inflammatory Properties and Adjuvant Potential of Synthetic Glycolipids Homologous to Mycolate Esters of the Cell Wall of <b><i>Mycobacterium tuberculosis</i></b>

Tima

Dulayymi²,

Denis³

et al. 2016

J Innate Immun

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Inflammatory properties and adjuvant potential of synthetic glycolipids homologous to mycolate esters of the cell wall of Mycobacterium tuberculosis.Hermann Giresse TIMA (1), Juma'a Raheem AL DULAYYMI (2), Olivier DENIS (1), Pauline LEHEBEL (1), Klarah Sherzad BAOLS (2), Mohsin Omar MOHAMMED (2), Laurent L'HOMME (3), Mohaned Mohammed SAHB (2), Georges POTEMBERG (1), Sylvie LEGRAND (3), Roland LANG (4), Rudi BEYAERT (5), Jacques PIETTE (3), MarkStephen BAIRD (2)#, Kris HUYGEN (1)#, Marta ROMANO (1)*#.

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Glucose monomycolates based on single synthetic mycolic acids

Cited by 8 publications

References 41 publications

Rational design of adjuvants targeting the C-type lectin Mincle

Rational design of adjuvants targeting the C-type lectin Mincle

CD1b-restricted GEM T cell responses are modulated byMycobacterium tuberculosismycolic acid meromycolate chains

Inflammatory Properties and Adjuvant Potential of Synthetic Glycolipids Homologous to Mycolate Esters of the Cell Wall of <b><i>Mycobacterium tuberculosis</i></b>

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