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Computationally designed bispecific MD2/CD14 binding peptides show TLR4 agonist activity

 
: Michaeli, Amit; Mezan, Shaul; Kühbacher, Andreas; Finkelmeier, Doris; Elias, Maayan; Zatsepin, Maria; Reed, Steven G.; Duthie, Malcolm S.; Rupp, Steffen; Lerner, Immanuel; Burger-Kentischer, Anke

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The Journal of immunology 201 (2018), Nr.11, S.3383-3391
ISSN: 0022-1767
ISSN: 1048-3233
ISSN: 1047-7381
ISSN: 1550-6606
Englisch
Zeitschriftenaufsatz
Fraunhofer IGB ()

Abstract
Toll-like receptor 4 plays an important role in the regulation of the innate and adaptive immune response. The majority of TLR4 activators currently in clinical use are derivatives of its prototypic ligand LPS. The discovery of innovative TLR4 activators has the potential of providing new therapeutic immunomodulators and adjuvants. We used computational design methods to predict and optimize a total of 53 cyclic and linear peptides targeting myeloid differentiation 2 (MD2) and cluster of differentiation 14 (CD14), both coreceptors of human TLR4. Activity of the designed peptides was first assessed using NF-κB reporter cell lines expressing either TLR4/MD2 or TLR4/CD14 receptors, then binding to CD14 and MD2 confirmed and quantified using MicroScale Thermophoresis. Finally, we incubated select peptides in human whole blood and observed their ability to induce cytokine production, either alone or in synergy with LPS. Our data demonstrate the advantage of computational design for the discovery of new TLR4 peptide activators with little structural resemblance to known ligands and indicate an efficient strategy with which to identify TLR4 targeting peptides that could be used as easy-to-produce alternatives to LPS-derived molecules in a variety of settings.

: http://publica.fraunhofer.de/dokumente/N-519806.html