Peptide drug for fibrosis

Designed RANKL fragment peptides (Partial agonist of RANKL) treat fibrosis.

Advantage and Core Benefit

  • Multiple functions of designed peptide
    • Inhibition of multiple TLR signaling through CD14 and RANK
    • Inhibition of TGF-β induced Smad2/3 phosphorylation and myofibroblast differentiation
    • Inhibition of Wnt/β-catenin signaling
  • Applicable for various inflammatory diseases

Background and Technology

Fibrosis is a chronic disease characterized by excessive accumulation of extracellular matrix and destruction of tissue structure in response to injury. Recently, the involvement of Toll-like receptors (TLRs) in the pathophysiology of lung fibrosis has been demonstrated as a key factor in the disease. TLRs recognize damage-associated molecular pattern (DAMP) released from injured epithelial cells, resulting in production of proinflammatory cytokines and profibrotic mediators that promote lung fibrosis. Some TLR inhibitors were reported to be effective in preclinical studies.

Researcher developed a partial RANKL peptide, named MHP1-AcN. This peptide exerts inhibitory effects on TLR 2, 3, 4, 7/8, and 9-mediated inflammatory cytokine production without inducing osteoclast activation. MHP1-AcN binds to CD14 and RANK, and its anti-inflammatory effect is dependent on both molecule. Taking advantage of this characteristic, they have examined its therapeutic effects in the following animal models: ischemic stroke, which is associated with TLR2 and TLR4; psoriasis associated with TLR7 and TLR8, and LPS-induced acute lung injury associated with TLR4 and TLR9. Based on this background, they demonstrated anti-fibrotic effect in vivo model.

In addition, activated Wnt/β-catenin signaling are known to play an important role in the development of fibrosis. LGR4 is R-spondin (RSPO) receptors mediating Wnt/β-catenin signaling. LGR4 also act as a second receptor for RANKL. MHP1-AcN compete with RSPO to interact with LGR4 and inhibit Wnt/β-catenin signaling.

The effect of MHP1-AcN, which was based on anti-fibrosis as well as anti-inflammatory effects, might provide a novel therapeutic strategy for the fibrosis.

Data

  • MHP1-AcN suppressed TGF-β/Smad signaling and TLR9 signaling in human fetal lung fibroblast (MRC-5) cells.
  • MHP1-AcN demonstrated anti-fibrotic effect in bleomycin induced fibrosis mouse model.
  • MHP1-AcN suppressed RSPO enhanced Wnt/β-catenin activity in HEK293 cells.

Patent and Publication

Researcher

Associate Prof. Munehisa Shimamura. (Graduate School of Medicine, Osaka University)

Expectations

We are seeking a partner who will commercialize therapeutic drugs based on this research project. If you hope the feasibility study of MHP1, please let us know. The researcher is welcome for collaborative research for the development of stroke, psoriasis, fibrosis, other inflammatory disease, or peptide optimization.

Project No: TT-03543

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