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.
Bibliographical noteFunding Information:
We thank the National Institutes of Health ( R01GM101279 and R01GM103843 to H.Y.) for the financial support.
© 2014 Elsevier Ltd. All rights reserved.
- Computational design
- Drug synergy
- Macrocyclic peptide
- Myeloid differentiation factor 2
- Toll-like receptor 4