Design of Trehalose-Based Amide/Sulfonamide C-type Lectin Receptor Signaling Compounds

Overview

Journal ChemMedChem

Specialties Chemistry
Pharmacology

Date 2021 Jan 8

PMID 33415819

Citations 9

Authors

Omer K Rasheed

Cassandra Buhl

Jay T Evans

Kendal T Ryter

Affiliations

Soon will be listed here.

Abstract

Mincle agonists have been shown to induce inflammatory cytokine production, such as tumor necrosis factor-alpha (TNF) and promote the development of a Th1/Th17 immune response that might be crucial to development of effective vaccination against pathogens such as Mycobacterium tuberculosis. As an expansion of our previous work, a library of 6,6'-amide and sulfonamide α,α-d-trehalose compounds with various substituents on the aromatic ring was synthesized efficiently in good to excellent yields. These compounds were evaluated for their ability to activate the human C-type lectin receptor Mincle by the induction of cytokines from human peripheral blood mononuclear cells. A preliminary structure-activity relationship (SAR) of these novel trehalose diamides and sulfonamides revealed that aryl amide-linked trehalose compounds demonstrated improved activity and relatively high potency cytokine production compared to the Mincle ligand trehalose dibehenate adjuvant (TDB) and the natural ligand trehalose dimycolate (TDM) inducing dose-dependent and human-Mincle-specific stimulation in a HEK reporter cell line.

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References

Jiang Y, Li S, Liu Y, Ge L, Han X, Liu Z . Synthesis and evaluation of trehalose-based compounds as novel inhibitors of cancer cell migration and invasion. Chem Biol Drug Des. 2015; 86(5):1017-29. DOI: 10.1111/cbdd.12569. View

Werninghaus K, Babiak A, Gross O, Holscher C, Dietrich H, Agger E . Adjuvanticity of a synthetic cord factor analogue for subunit Mycobacterium tuberculosis vaccination requires FcRgamma-Syk-Card9-dependent innate immune activation. J Exp Med. 2009; 206(1):89-97. PMC: 2626670. DOI: 10.1084/jem.20081445. View

Jegouzo S, Harding E, Acton O, Rex M, Fadden A, Taylor M . Defining the conformation of human mincle that interacts with mycobacterial trehalose dimycolate. Glycobiology. 2014; 24(12):1291-300. PMC: 4211601. DOI: 10.1093/glycob/cwu072. View

Rose J, Maddry J, Comber R, Suling W, Wilson L, Reynolds R . Synthesis and biological evaluation of trehalose analogs as potential inhibitors of mycobacterial cell wall biosynthesis. Carbohydr Res. 2002; 337(2):105-20. DOI: 10.1016/s0008-6215(01)00288-9. View

Foster A, Kodar K, Timmer M, Stocker B . ortho-Substituted lipidated Brartemicin derivative shows promising Mincle-mediated adjuvant activity. Org Biomol Chem. 2019; 18(6):1095-1103. DOI: 10.1039/c9ob02397f. View

Kimura A, Kishimoto T . IL-6: regulator of Treg/Th17 balance. Eur J Immunol. 2010; 40(7):1830-5. DOI: 10.1002/eji.201040391. View

Thota N, Makam P, Rajbongshi K, Nagiah S, Abdul N, Chuturgoon A . -Trifluoromethylthiolated Sulfonimidamides and Sulfoximines: Anti-microbial, Anti-mycobacterial, and Cytotoxic Activity. ACS Med Chem Lett. 2019; 10(10):1457-1461. PMC: 6792286. DOI: 10.1021/acsmedchemlett.9b00285. View

Jiang Y, Tang L, Miyanaga S, Igarashi Y, Saiki I, Liu Z . Synthesis and evaluation of trehalose-based compounds as anti-invasive agents. Bioorg Med Chem Lett. 2011; 21(4):1089-91. DOI: 10.1016/j.bmcl.2010.12.133. View

Bird J, Khan A, Nishimura N, Yamasaki S, Timmer M, Stocker B . Synthesis of Branched Trehalose Glycolipids and Their Mincle Agonist Activity. J Org Chem. 2018; 83(15):7593-7605. DOI: 10.1021/acs.joc.7b03269. View

10.

Ryter K, Ettenger G, Rasheed O, Buhl C, Child R, Miller S . Aryl Trehalose Derivatives as Vaccine Adjuvants for . J Med Chem. 2019; 63(1):309-320. PMC: 6952572. DOI: 10.1021/acs.jmedchem.9b01598. View

11.

Matsumoto M, Tanaka T, Kaisho T, Sanjo H, Copeland N, Gilbert D . A novel LPS-inducible C-type lectin is a transcriptional target of NF-IL6 in macrophages. J Immunol. 1999; 163(9):5039-48. View

12.

Stocker B, Kodar K, Wahi K, Foster A, Harper J, Mori D . The effects of trehalose glycolipid presentation on cytokine production by GM-CSF macrophages. Glycoconj J. 2019; 36(1):69-78. DOI: 10.1007/s10719-018-09857-9. View

13.

Mohanraj M, Sekar P, Liou H, Chang S, Lin W . The Mycobacterial Adjuvant Analogue TDB Attenuates Neuroinflammation via Mincle-Independent PLC-γ1/PKC/ERK Signaling and Microglial Polarization. Mol Neurobiol. 2018; 56(2):1167-1187. DOI: 10.1007/s12035-018-1135-4. View

14.

Feinberg H, Jegouzo S, Rowntree T, Guan Y, Brash M, Taylor M . Mechanism for recognition of an unusual mycobacterial glycolipid by the macrophage receptor mincle. J Biol Chem. 2013; 288(40):28457-65. PMC: 3789947. DOI: 10.1074/jbc.M113.497149. View

15.

Yamamoto H, Oda M, Nakano M, Watanabe N, Yabiku K, Shibutani M . Development of vizantin, a safe immunostimulant, based on the structure-activity relationship of trehalose-6,6'-dicorynomycolate. J Med Chem. 2012; 56(1):381-5. DOI: 10.1021/jm3016443. View

16.

Ottenhoff T, Doherty T, van Dissel J, Bang P, Lingnau K, Kromann I . First in humans: a new molecularly defined vaccine shows excellent safety and strong induction of long-lived Mycobacterium tuberculosis-specific Th1-cell like responses. Hum Vaccin. 2010; 6(12):1007-15. DOI: 10.4161/hv.6.12.13143. View

17.

Desel C, Werninghaus K, Ritter M, Jozefowski K, Wenzel J, Russkamp N . The Mincle-activating adjuvant TDB induces MyD88-dependent Th1 and Th17 responses through IL-1R signaling. PLoS One. 2013; 8(1):e53531. PMC: 3538599. DOI: 10.1371/journal.pone.0053531. View

18.

Lee S, Nguyen M . Recent advances of vaccine adjuvants for infectious diseases. Immune Netw. 2015; 15(2):51-7. PMC: 4411509. DOI: 10.4110/in.2015.15.2.51. View

19.

Percec V, Wilson D, Leowanawat P, Wilson C, Hughes A, Kaucher M . Self-assembly of Janus dendrimers into uniform dendrimersomes and other complex architectures. Science. 2010; 328(5981):1009-14. DOI: 10.1126/science.1185547. View

20.

Jacobsen K, Keiding U, Clement L, Schaffert E, Rambaruth N, Johannsen M . The natural product brartemicin is a high affinity ligand for the carbohydrate-recognition domain of the macrophage receptor mincle. Medchemcomm. 2015; 6(4):647-652. PMC: 4393326. DOI: 10.1039/c4md00512k. View