Rationally Designed Macrocyclic Peptides as Synergistic Agonists of LPS-Induced Inflammatory Response.
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 theRosetta Macromolecular Modelingsoftware. 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 lead to valuable tools for the investigation of TLR4 signaling.
Center of Basic Molecular Science and Department of Chemistry, Tsinghua University, Beijing, China, 100082.
Meng
M
Gao
Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, Hadassah Medical School, The Hebrew University, POB 12272, Jerusalem, 91120 Israel.
Nir
N
London
Department of Chemistry and Biochemistry, the BioFrontiers Institute, University of Colorado Boulder, Boulder, Colorado 80309-0596, USA.
Kui
K
Cheng
Department of Chemistry and Biochemistry, the BioFrontiers Institute, University of Colorado Boulder, Boulder, Colorado 80309-0596, USA.
Ryo
R
Tamura
Center of Basic Molecular Science and Department of Chemistry, Tsinghua University, Beijing, China, 100082.
Jialin
J
Jin
Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, Hadassah Medical School, The Hebrew University, POB 12272, Jerusalem, 91120 Israel.
Ora
O
Schueler-Furman
Center of Basic Molecular Science and Department of Chemistry, Tsinghua University, Beijing, China, 100082.|Department of Chemistry and Biochemistry, the BioFrontiers Institute, University of Colorado Boulder, Boulder, Colorado 80309-0596, USA.
Hang
H
Yin
Computer design; Drug synergy; Macrocyclic peptide; Myeloid differentiation factor 2; Toll-like receptor 4