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Published on: September 30, 2019
Identification of peptide inhibitors of transforming growth factor beta 1 using a phage-displayed peptide library
Javier Dotor1, Ana B López-Vázquez, Juan J Lasarte
1Division of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), University of Navarra, Avda. Pío XII, 55-31008-Pamplona, Spain. jdotor@unav.es
Abstract:
Pathologies such as liver fibrosis and scleroderma are characterized by harmful levels of transforming growth factor beta 1 (TGFbeta1). These levels could be neutralized if inhibitors of this cytokine were available. With this aim we searched for peptides with binding affinity for TGFbeta1 using a phage-displayed random 15-mer peptide library. Some peptides thus identified blocked activity of TGFbeta1 in vitro, as measured by their capacity to restore growth of Mv-1-Lu cells in presence of added TGFbeta1. Also, they inhibited TGFbeta1-dependent expression of collagen type I mRNA in liver of mice orally insulted with CCl(4). Intraperitoneal administration of 50 microg of peptide P17 (the most active 15-mer peptide, also referred to as P17(1-15)) inhibited expression of collagen type I mRNA by almost 100%. Interestingly, titration experiments showed that P17(1-12) (a peptide encompassing the first 12 amino acids of P17) was approximately four times more active than P17. These results suggest that both peptides, as well as others reported here, may be of therapeutic interest in processes requiring control of undesired high levels of TGFbeta1.
Insights
Researchers identified novel peptides that inhibit transforming growth factor beta 1 (TGFbeta1), a key factor in liver fibrosis and scleroderma. These TGFbeta1 inhibitors show therapeutic potential for conditions with elevated TGFbeta1 levels.
Area of Science:
- Biochemistry
- Molecular Biology
- Immunology
Background:
- Pathological conditions like liver fibrosis and scleroderma involve elevated levels of transforming growth factor beta 1 (TGFbeta1).
- Neutralizing excessive TGFbeta1 activity could offer therapeutic benefits for these diseases.
Purpose of the Study:
- To discover peptides that bind to and inhibit the activity of TGFbeta1.
- To evaluate the therapeutic potential of identified peptides in preclinical models.
Main Methods:
- Phage display technology was used to screen a random 15-mer peptide library for binding to TGFbeta1.
- In vitro assays measured the ability of identified peptides to block TGFbeta1 activity by restoring cell growth.
- In vivo studies assessed the inhibition of TGFbeta1-dependent collagen type I mRNA expression in a mouse model of liver fibrosis.
Main Results:
- Several peptides were identified that bind to TGFbeta1 and inhibit its activity in vitro.
- These peptides demonstrated efficacy in reducing TGFbeta1-dependent collagen type I mRNA expression in vivo.
- Peptide P17 and its truncated form P17(1-12) showed significant inhibitory effects, with P17(1-12) being more potent.
Conclusions:
- Novel peptides capable of inhibiting TGFbeta1 activity have been identified.
- These peptides, particularly P17 and P17(1-12), represent promising therapeutic candidates for diseases characterized by high TGFbeta1 levels.
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