title: Prevention of bleomycin-induced pulmonary fibrosis by a novel antifibrotic peptide with relaxin-like activity.
abstract: Pulmonary fibrosis is a progressive and lethal lung disease characterized by accumulation of extracellular matrix and loss of pulmonary function. No cure exists for this pathologic condition, and current treatments often fail to slow its progression or relieve its symptoms. Relaxin was previously shown to induce a matrix-degrading phenotype in human lung fibroblasts in vitro and to inhibit pulmonary fibrosis in vivo. A novel peptide that targets the relaxin RXFP1/LGR7 receptor was recently identified using our computational platform designed to predict novel G protein-coupled receptor peptide agonists. In this study, we examined the antifibrotic properties of this novel peptide, designated CGEN25009, in human cell-based assays and in a murine model of bleomycin-induced pulmonary fibrosis. Similar to relaxin, CGEN25009 was found to have an inhibitory effect on transforming growth factor-β1-induced collagen deposition in human dermal fibroblasts and to enhance MMP-2 expression. The peptide's biological activity was also similar to relaxin in generating cellular stimulation of cAMP, cGMP, and NO in the THP-1 human cell line. In vivo, 2-week administration of CGEN25009 in a preventive or therapeutic mode (i.e., concurrently with or 7 days after bleomycin treatment, respectively) caused a significant reduction in lung inflammation and injury and ameliorated adverse airway remodeling and peribronchial fibrosis. The results of this study indicate that CGEN25009 displays antifibrotic and anti-inflammatory properties and may offer a new therapeutic option for the treatment of pulmonary fibrosis.
authors.affiliation: Compugen Ltd, Tel Aviv, Israel.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pini
authors.forename: Ronen
authors.initials: R
authors.lastname: Shemesh
authors.forename: Chrishan S
authors.initials: CS
authors.lastname: Samuel
authors.forename: Ross A D
authors.initials: RA
authors.lastname: Bathgate
authors.forename: Arie
authors.initials: A
authors.lastname: Zauberman
authors.forename: Chen
authors.initials: C
authors.lastname: Hermesh
authors.forename: Assaf
authors.initials: A
authors.lastname: Wool
authors.forename: Daniele
authors.initials: D
authors.lastname: Bani
authors.forename: Galit
authors.initials: G
authors.lastname: Rotman
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D001980:Bronchi / Q000473:pathology; D045744:Cell Line, Tumor; D003094:Collagen / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D020397:Goblet Cells / Q000473:pathology; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009130:Muscle, Smooth / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D009195:Peroxidase / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000378:metabolism; D018000:Receptors, Peptide / Q000819:agonists / Q000378:metabolism; D012065:Relaxin / Q000819:agonists* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: C555537:CGEN250090 peptide; D010455:Peptides; C095068:RLN2 protein, human; C417543:RXFP1 protein, human; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; D017392:Thiobarbituric Acid Reactive Substances; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D012065:Relaxin; D003094:Collagen; D000242:Cyclic AMP; D009195:Peroxidase; D020778:Matrix Metalloproteinase 2; D006152:Cyclic GMP