TY - JOUR
T1 - Rationally designed macrocyclic peptides as synergistic agonists of LPS-induced inflammatory response
AU - Gao, Meng
AU - London, Nir
AU - Cheng, Kui
AU - Tamura, Ryo
AU - Jin, Jialin
AU - Schueler-Furman, Ora
AU - Yin, Hang
N1 - Publisher Copyright:
© 2014 Elsevier Ltd. All rights reserved.
PY - 2014/10/21
Y1 - 2014/10/21
N2 - 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.
AB - 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.
KW - Computational design
KW - Drug synergy
KW - Macrocyclic peptide
KW - Myeloid differentiation factor 2
KW - Toll-like receptor 4
UR - http://www.scopus.com/inward/record.url?scp=84907940003&partnerID=8YFLogxK
U2 - 10.1016/j.tet.2014.07.026
DO - 10.1016/j.tet.2014.07.026
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AN - SCOPUS:84907940003
SN - 0040-4020
VL - 70
SP - 7664
EP - 7668
JO - Tetrahedron
JF - Tetrahedron
IS - 42
ER -