title: 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.
abstract: 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.
authors.affiliation: College of Pharmaceutical Sciences, Southwest University , Chongqing 400715, China.
authors.forename: Luying
authors.initials: L
authors.lastname: Huang
authors.affiliation: College of Pharmaceutical Sciences, Southwest University , Chongqing 400715, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xie
authors.affiliation: College of Pharmaceutical Sciences, Southwest University , Chongqing 400715, China.
authors.forename: Qiuyan
authors.initials: Q
authors.lastname: Bi
authors.affiliation: College of Pharmaceutical Sciences, Southwest University , Chongqing 400715, China.
authors.forename: Zhuoxuan
authors.initials: Z
authors.lastname: Li
authors.affiliation: College of Pharmaceutical Sciences, Southwest University , Chongqing 400715, China.
authors.forename: Sha
authors.initials: S
authors.lastname: Liu
authors.affiliation: School of Pharmacy, Key Laboratory of Smart Drug Delivery, Ministry of Education, Fudan University , Shanghai 201203, China.|State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai 200032, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Shen
authors.affiliation: College of Pharmaceutical Sciences, Southwest University , Chongqing 400715, China.
authors.forename: Chong
authors.identifier: 0000-0002-6049-7675
authors.initials: C
authors.lastname: Li
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D002460:Cell Line; D003474:Curcumin / Q000737:chemistry / Q000627:therapeutic use*; D004705:Endocytosis / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008081:Liposomes / Q000737:chemistry; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D051379:Mice; D010455:Peptides / Q000737:chemistry / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics*; D000074050:TWEAK Receptor / Q000819:agonists / Q000378:metabolism*
chemical_list: D008081:Liposomes; D010455:Peptides; D012333:RNA, Messenger; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; D002251:Carbon Tetrachloride; D003474:Curcumin
keywords: curcumin; liposomes; liver fibrosis; mirror-image mRNA display