Rationally designed macrocyclic peptides as synergistic agonists of LPS-induced inflammatory response

Meng Gao, Nir London, Kui Cheng, Ryo Tamura, Jialin Jin, Ora Schueler-Furman*, Hang Yin

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


Toll-like receptor 4 (TLR4) plays an important role in the regulation of the innate and adaptive immune response. Both agonists and antagonists of TLR4 are of considerable interest as drug leads for various disease indications. We herein report the rational design of two myeloid differentiation factor 2 (MD2)-derived macrocyclic peptides as TLR4 modulators, using the Rosetta Macromolecular Modeling software. The designed cyclic peptides, but not their linear counterparts, displayed synergistic activation of TLR signaling when co-administered with lipopolysaccharide (LPS). Although the understanding of the mechanism of action of these peptides remains elusive, these results underscore the utility of peptide cyclization for the discovery of biologically active agents, and also provide valuable tools for the investigation of TLR4 signaling.

Original languageAmerican English
Pages (from-to)7664-7668
Number of pages5
Issue number42
StatePublished - 21 Oct 2014

Bibliographical note

Publisher Copyright:
© 2014 Elsevier Ltd. All rights reserved.


  • Computational design
  • Drug synergy
  • Macrocyclic peptide
  • Myeloid differentiation factor 2
  • Toll-like receptor 4


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