2 research outputs found
Highly Selective Targeting of Hepatic Stellate Cells for Liver Fibrosis Treatment Using a d‑Enantiomeric Peptide Ligand of Fn14 Identified by Mirror-Image mRNA Display
Although
liver fibrosis is a major public health issue, there is
still no effective drug therapy in the clinic. Fibroblast growth factor-inducible
14 (Fn14), a membrane receptor highly specifically expressed in activated
hepatic stellate cells (HSCs), is the key driver of liver fibrosis,
and thus, it has a great potential as a novel target for the development
of effective treatment. Here, we identified a d-enantiomeric
peptide ligand of Fn14 through mirror-image mRNA display. This included
the chemical synthesis of a d-enantiomer of the target protein
(extracellular domain of Fn14), identification of an l-peptide
ligand of d-Fn14 using a constructed mRNA peptide library,
and identification of a d-enantiomer of the l-peptide,
which is a ligand of the natural Fn14 for reasons of symmetry. The
obtained d-peptide ligand showed strong binding to Fn14 while
maintaining high proteolytic resistance. As a targeting moiety, this d-peptide successfully mediated high selectivity of activated
HSCs for liposomal vehicles compared to that of other major cell types
in the liver and significantly enhanced the accumulation of liposomes
in the liver fibrosis region of a carbon tetrachloride-induced mouse
model. Moreover, in combination with curcumin as an encapsulated load,
a liposomal formulation conjugated with this d-peptide showed
powerful inhibition of the proliferation of activated HSCs and reduced
the liver fibrosis to a significant extent in vivo. This Fn14-targeting
strategy may represent a promising approach to targeted drug delivery
for liver fibrosis treatment. Meanwhile, the mirror-image mRNA display
can provide a new arsenal for the development of d-peptide-based
therapeutics against a variety of human diseases
Highly Selective Targeting of Hepatic Stellate Cells for Liver Fibrosis Treatment Using a d‑Enantiomeric Peptide Ligand of Fn14 Identified by Mirror-Image mRNA Display
Although
liver fibrosis is a major public health issue, there is
still no effective drug therapy in the clinic. Fibroblast growth factor-inducible
14 (Fn14), a membrane receptor highly specifically expressed in activated
hepatic stellate cells (HSCs), is the key driver of liver fibrosis,
and thus, it has a great potential as a novel target for the development
of effective treatment. Here, we identified a d-enantiomeric
peptide ligand of Fn14 through mirror-image mRNA display. This included
the chemical synthesis of a d-enantiomer of the target protein
(extracellular domain of Fn14), identification of an l-peptide
ligand of d-Fn14 using a constructed mRNA peptide library,
and identification of a d-enantiomer of the l-peptide,
which is a ligand of the natural Fn14 for reasons of symmetry. The
obtained d-peptide ligand showed strong binding to Fn14 while
maintaining high proteolytic resistance. As a targeting moiety, this d-peptide successfully mediated high selectivity of activated
HSCs for liposomal vehicles compared to that of other major cell types
in the liver and significantly enhanced the accumulation of liposomes
in the liver fibrosis region of a carbon tetrachloride-induced mouse
model. Moreover, in combination with curcumin as an encapsulated load,
a liposomal formulation conjugated with this d-peptide showed
powerful inhibition of the proliferation of activated HSCs and reduced
the liver fibrosis to a significant extent in vivo. This Fn14-targeting
strategy may represent a promising approach to targeted drug delivery
for liver fibrosis treatment. Meanwhile, the mirror-image mRNA display
can provide a new arsenal for the development of d-peptide-based
therapeutics against a variety of human diseases