Synthetic glycan-based TLR4 agonists targeting caspase-4/11 for the development of adjuvants and immunotherapeutics.

Chemical Science
Florian AdanitschAlla Zamyatina

Abstract

Gram-negative bacterial lipopolysaccharide (LPS)-induced Toll-like receptor 4 (TLR4) mediated pro-inflammatory signaling plays a key role in immunoprotection against infectious challenges and boosts adaptive immunity, whereas the activation of the cytosolic LPS receptor caspase-4/11 leads to cell death by pyroptosis and is deeply implicated in the development of sepsis. Despite tremendous advances in the understanding of the LPS-TLR4 interaction, predictably regulated TLR4 activation has not yet been achieved. The structural basis for the induction of caspase-4/11 protease activity by LPS is currently unknown. The modulation of innate and adaptive immune responses through the controlled induction of TLR4 signaling without triggering caspase-4/11 activity would open novel perspectives in the development of safe vaccine adjuvants and immunotherapeutics. We report the discovery of highly potent glycan-based immunostimulants with picomolar affinity for TLR4 which interact with caspase-4/11 and promote caspase-4/11 oligomerization while abolishing caspase-11 protease activity. The rigidity and twisted molecular shape of the α,α-(1↔1')-linked disaccharide core of synthetic LPS mimicking anionic glycolipids accounted for both species-...Continue Reading

References

Sep 30, 2004·Nature Immunology·Akiko Iwasaki, Ruslan Medzhitov
Apr 25, 2007·International Journal of Medical Microbiology : IJMM·Steven M Opal
Jun 16, 2007·Science·Verónica Mata-HaroThomas C Mitchell
Jul 27, 2007·Nature Clinical Practice. Cardiovascular Medicine·Stefan FrantzJohann Bauersachs
Jun 11, 2008·Cell Host & Microbe·Ken J IshiiShizuo Akira
Aug 1, 2008·Cellular and Molecular Life Sciences : CMLS·C R Casella, T C Mitchell
Aug 15, 2008·Immunity·Mi Sun Jin, Jie-Oh Lee
Jan 16, 2009·Chembiochem : a European Journal of Chemical Biology·Sampat IngaleGeert-Jan Boons
Mar 27, 2009·The Journal of Biological Chemistry·Nusa ResmanRoman Jerala
May 29, 2009·Pharmacological Reviews·Luke A J O'NeillSarah L Doyle
Dec 19, 2009·The Journal of Biological Chemistry·Jianmin MengDouglas T Golenbock
Jan 22, 2010·Organic & Biomolecular Chemistry·Laurel K Mydock, Alexei V Demchenko
Jul 2, 2010·The New England Journal of Medicine·Richard S Hotchkiss, Steven Opal
Jan 11, 2011·Nature Medicine·Bolormaa VandanmagsarVishwa Deep Dixit
Apr 26, 2012·Proceedings of the National Academy of Sciences of the United States of America·Umeharu OhtoToshiyuki Shimizu
May 16, 2012·Proceedings of the National Academy of Sciences of the United States of America·Yanyan LiRobert K Ernst
Jan 9, 2013·Proceedings of the National Academy of Sciences of the United States of America·Brittany D NeedhamM Stephen Trent
Jan 16, 2013·Current Opinion in Microbiology·Gregory I VladimerEgil Lien
Jan 17, 2013·Proceedings of the National Academy of Sciences of the United States of America·Jean-Philippe MichaudSerge Rivest
Apr 18, 2013·American Journal of Respiratory and Critical Care Medicine·Jenneke LeentjensPeter Pickkers
May 3, 2013·Nature·Kari Ann ShireyStefanie N Vogel
May 3, 2013·PloS One·Carolyn R Casella, Thomas C Mitchell
Jul 28, 2013·Science·Nobuhiko KayagakiVishva M Dixit
Sep 14, 2013·Science·Jonathan C Kagan
Nov 16, 2013·Nature Reviews. Immunology·Richard S HotchkissDidier Payen
Mar 4, 2014·Current Opinion in Microbiology·Jon A Hagar, Edward A Miao
Sep 26, 2014·Journal of Medicinal Chemistry·Florian AdanitschAlla Zamyatina
Oct 1, 2014·Cell Research·Jon Alan HagarEdward Axel Miao
Jan 27, 2015·Current Opinion in Immunology·Jieling YangFeng Shao
Mar 24, 2015·Expert Review of Vaccines·Afshin Zariri, Peter van der Ley
Jun 13, 2015·Proceedings of the National Academy of Sciences of the United States of America·Svasti Haricharan, Powel Brown
Feb 3, 2016·Proceedings of the National Academy of Sciences of the United States of America·Ying WangBruce Beutler
Apr 25, 2017·Nature Reviews. Immunology·Tom van der PollMihai G Netea
May 11, 2017·MBio·Kelsey A GreggRobert K Ernst
May 30, 2017·Chemical Science·S van der VormJ D C Codée
Sep 1, 2017·Nature Cell Biology·Brent E Fitzwalter, Andrew Thorburn
Jan 31, 2018·Beilstein Journal of Organic Chemistry·Alla Zamyatina

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Citations

Aug 9, 2020·Frontiers in Immunology·Alessio Romerio, Francesco Peri
Jan 28, 2021·International Journal of Molecular Sciences·Laura Kate GadanecVasso Apostolopoulos
Feb 2, 2021·Nature Reviews. Chemistry·Carlo PifferiAlberto Fernández-Tejada
Apr 6, 2021·Frontiers in Immunology·Holger HeineAlla Zamyatina
Sep 19, 2018·Molecular Pharmaceutics·Maryam A Shetab Boushehri, Alf Lamprecht
Sep 12, 2020·Chemical Reviews·Wen-Hao Li, Yan-Mei Li
Aug 29, 2021·Pharmacology & Therapeutics·Pilar Garcia-VelloAntonio Molinaro

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Methods Mentioned

BETA
acylation
glycosylation
electrophoresis
chemical modifications

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