640291-21-0Relevant academic research and scientific papers
Self-Adjuvanting Cancer Vaccines from Conjugation-Ready Lipid A Analogues and Synthetic Long Peptides
Reintjens, Niels R. M.,Tondini, Elena,De Jong, Ana R.,Meeuwenoord, Nico J.,Chiodo, Fabrizio,Peterse, Evert,Overkleeft, Herman S.,Filippov, Dmitri V.,Van Der Marel, Gijsbert A.,Ossendorp, Ferry,Codée, Jeroen D. C.
, p. 11691 - 11706 (2020/11/26)
Self-adjuvanting vaccines, wherein an antigenic peptide is covalently bound to an immunostimulating agent, have been shown to be promising tools for immunotherapy. Synthetic Toll-like receptor (TLR) ligands are ideal adjuvants for covalent linking to peptides or proteins. We here introduce a conjugation-ready TLR4 ligand, CRX-527, a potent powerful lipid A analogue, in the generation of novel conjugate-vaccine modalities. Effective chemistry has been developed for the synthesis of the conjugation-ready ligand as well as the connection of it to the peptide antigen. Different linker systems and connection modes to a model peptide were explored, and in vitro evaluation of the conjugates showed them to be powerful immune-activating agents, significantly more effective than the separate components. Mounting the CRX-527 ligand at the N-terminus of the model peptide antigen delivered a vaccine modality that proved to be potent in activation of dendritic cells, in facilitating antigen presentation, and in initiating specific CD8+ T-cell-mediated killing of antigen-loaded target cells in vivo. Synthetic TLR4 ligands thus show great promise in potentiating the conjugate vaccine platform for application in cancer vaccination.
The 'Ethereal' nature of TLR4 agonism and antagonism in the AGP class of lipid A mimetics
Bazin, Helene G.,Murray, Tim J.,Bowen, William S.,Mozaffarian, Afsaneh,Fling, Steven P.,Bess, Laura S.,Livesay, Mark T.,Arnold, Jeffrey S.,Johnson, Craig L.,Ryter, Kendal T.,Cluff, Christopher W.,Evans, Jay T.,Johnson, David A.
scheme or table, p. 5350 - 5354 (2009/08/07)
To overcome the chemical and metabolic instability of the secondary fatty acyl residues in the AGP class of lipid A mimetics, the secondary ether lipid analogs of the potent TLR4 agonist CRX-527 (2) and TLR4 antagonist CRX-526 (3) were synthesized and evaluated along with their ester counterparts for agonist/antagonist activity in both in vitro and in vivo models. Like CRX-527, the secondary ether lipid 4 showed potent agonist activity in both murine and human models. Ether lipid 5, on the other hand, showed potent TLR4 antagonist activity similar to CRX-526 in human cell assays, but did not display any antagonist activity in murine models and, in fact, was weakly agonistic. Glycolipids 2, 4, and 5 were synthesized via a new highly convergent method utilizing a common advanced intermediate strategy. A new method for preparing (R)-3-alkyloxytetradecanoic acids, a key component of ether lipids 4 and 5, is also described.
