Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Jul 15;28(14):115564.
doi: 10.1016/j.bmc.2020.115564. Epub 2020 May 31.

6,6'-Aryl trehalose analogs as potential Mincle ligands

Omer K Rasheed  1 , George Ettenger  1 , Cassandra Buhl  2 , Robert Child  2 , Shannon M Miller  2 , Jay T Evans  3 , Kendal T Ryter  4
Affiliations

6,6'-Aryl trehalose analogs as potential Mincle ligands

Omer K Rasheed et al. Bioorg Med Chem. .

Abstract

6,6'-Aryl trehalose derivatives have been synthesized with a view towards identifying novel Th-17-inducing vaccine adjuvants based on the high affinity Mincle ligand Brartemicin. The initial structure-activity relationships of these novel trehalose-based compounds were investigated. All compounds have been evaluated for their ability to engage the Mincle receptor and induce a potential pro-Th17 cytokine profile from human peripheral blood mononuclear cells based on IL-6 production in human peripheral blood mononuclear cells. The preliminary biological characterization of the designed analogs presented in this paper should aid in the future design and testing of more affine ligands that may foster the discovery of novel adjuvants with improved pharmacological properties.

Keywords: Adjuvant; Brartemicin; Mincle; TH-17; Trehalose diester; Trehalose dimycolate; Tuberculosis; Vaccine.

PubMed Disclaimer

Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Figure 1.
Figure 1.
Representative Mincle ligands: Trehalose Dimycolates (TDM), α-Trehalose Diesters (Vizantin), Trehalose Dicorynomycolates (TDCM), Trehalose dibehenate (TDB), Brartemicin analogs and UM1024.
Figure 2:
Figure 2:
Cytokine production from primary human mononuclear cells in response to stimulation with synthetic compounds; The indicated compound was dissolved in ethanol and dried to the bottom of a tissue culture plate. hPBMCs were added and incubated at 37 °C for 18–24 hours. IL-6 secretion was measured by ELISA; n=3 independent donors for all experiments; error bars indicate SEM.
Figure 3:
Figure 3:
(a-c) Activation of human Mincle in response to synthesized library. The indicated compounds were plate coated in EtOH and HEK cells transfected with human Mincle and an NF-κB-driven SEAP reporter were added and incubated with the compounds for 18–24 hour followed by assessment of the supernatants for SEAP levels. Data are represented as fold change in OD650 over vehicle treated cells. n=3 for all experiments; error bars indicate SEM. (d) results in HEK null cells.
Scheme 1:
Scheme 1:. Reagents and reaction conditions:
i) BSA, TBAF, DMF; ii) K2CO3, MeOH (90%); iii) (CF3SO2)2O, pyridine, DCM (95%); iv) K salt of acid, 18-crown ether, toluene, 80 °C (40–85%); v) aryl acid, EDCI-MeI, DMAP, DCM or aryl acid, DCC, DMAP, DCM (30–90%); vi) Dowex-H+, DCM:MeOH (1:1) (70–90%). a) conditions iii, iv were used; b) conditions v were used
See this image and copyright information in PMC

References

    1. Patil K; Bagade S; Bonde S; Sharma S; Saraogi G; Biomed. & Pharm, 2018, 99, 735–745; - PubMed
    2. Swarts MB; Holsclaw CM; Jewett JC; Alber M; Fox DM; Siegrist M,S; Leary JA; Kalscheuer R; Bertozzi CR, J. Am. Chem. Soc, 2012, 134, 16123–16126; - PMC - PubMed
    3. Backus K,M; Boshoff H,I; Barry CS; Boutureira O; Patel MK; D’Hooge F; Lee SS; Via LE, Tahlan K, Barry CE III; Davis BG; Nat. Chem. Bio, 2011, 7, 228–235; - PMC - PubMed
    4. Winslow GM; Cooper A; Reiley W; Chatterjee M; Woodland DL; Immunol. Rev, 2008, 225, 284–299; - PMC - PubMed
    5. Daniel TM, Respir. Med, 2006, 100(11), 1862–1870. - PubMed
    1. WHO, Global tuberculosis report 2019. Geneva: World Health Organization; 2019.
    1. Schrager LK; Harris RC; Vekemans J; F1OOORes, 2018, 7, 1732. - PMC - PubMed
    1. Copland A; Diogo GR; Hart P; Harris S; Tran AC; Paul MJ; Singh M; Cutting SM; Reljic R; Front. Immunol, 2018, 9, 346; - PMC - PubMed
    2. Moliva JI; Turner J; Torrelles JB; 2017, Front. Immunol, 8, 407–424; - PMC - PubMed
    3. Andersen P; Doherty TM, Nat. Rev. Microbiol, 2005, 3 (8), 656–62; - PubMed
    4. Colditz GA; Brewer TF; Berkey CS; Wilson ME; Burdick E; Fineberg HV; Mosteller F, JAMA, 1994, 271 (9), 698–702. - PubMed
    1. Foged C, Therapeutic Delivery, 2011, 2(8), 1057–1077. - PubMed

Publication types

MeSH terms

LinkOut - more resources