A viral insulin-like peptide is a natural competitive antagonist of the human IGF-1 receptor
Objective: Natural sources of molecular diversity remain of utmost importance as a reservoir of proteins and peptides with unique biological functions. We recently identified such a family of viral insulin-like peptides (VILPs). We sought to advance the chemical methods in synthesis to explore the s...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-11-01
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| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877821001630 |
| _version_ | 1818927695502770176 |
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| author | Fa Zhang Emrah Altindis C. Ronald Kahn Richard D. DiMarchi Vasily Gelfanov |
| author_facet | Fa Zhang Emrah Altindis C. Ronald Kahn Richard D. DiMarchi Vasily Gelfanov |
| author_sort | Fa Zhang |
| collection | DOAJ |
| description | Objective: Natural sources of molecular diversity remain of utmost importance as a reservoir of proteins and peptides with unique biological functions. We recently identified such a family of viral insulin-like peptides (VILPs). We sought to advance the chemical methods in synthesis to explore the structure-function relationship within these VILPs, and the molecular basis for differential biological activities relative to human IGF-1 and insulin. Methods: Optimized chemical methods in synthesis were established for a set of VILPs and related analogs. These modified forms included the substitution of select VILP chains with those derived from human insulin and IGF-1. Each peptide was assessed in vitro for agonism and antagonism at the human insulin and the human insulin-like growth factor 1 receptor (IGF-1R). Results: We report here that one of these VILPs, lymphocystis disease virus-1 (LCDV1)-VILP, has the unique property to be a potent and full antagonist of the IGF-1R. We demonstrate the coordinated importance of the B- and C-chains of the VILP in regulating this activity. Moreover, mutation of the glycine following the first cysteine in the B-chain of IGF-1 to serine, in concert with substitution to the connecting peptide of LCDV1-VILP, converted native IGF-1 to a high potency antagonist. Conclusions: The results reveal novel aspects in ligand–receptor interactions at the IGF-1 receptor and identify a set of antagonists of potential medicinal importance. |
| first_indexed | 2024-12-20T03:17:06Z |
| format | Article |
| id | doaj.art-f3711ebfbba144dcbe3bf20dd8d9d17b |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-12-20T03:17:06Z |
| publishDate | 2021-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-f3711ebfbba144dcbe3bf20dd8d9d17b2022-12-21T19:55:20ZengElsevierMolecular Metabolism2212-87782021-11-0153101316A viral insulin-like peptide is a natural competitive antagonist of the human IGF-1 receptorFa Zhang0Emrah Altindis1C. Ronald Kahn2Richard D. DiMarchi3Vasily Gelfanov4Department of Chemistry, Indiana University, Bloomington, IN, 47405, USABoston College Biology Department, Chestnut Hill, MA, 02467, USAJoslin Diabetes Center, Harvard Medical School, Boston, MA, 02215, USADepartment of Chemistry, Indiana University, Bloomington, IN, 47405, USA; Corresponding author.Novo Nordisk Research Center, 5225 Exploration Drive, Indianapolis, IN, 46241, USAObjective: Natural sources of molecular diversity remain of utmost importance as a reservoir of proteins and peptides with unique biological functions. We recently identified such a family of viral insulin-like peptides (VILPs). We sought to advance the chemical methods in synthesis to explore the structure-function relationship within these VILPs, and the molecular basis for differential biological activities relative to human IGF-1 and insulin. Methods: Optimized chemical methods in synthesis were established for a set of VILPs and related analogs. These modified forms included the substitution of select VILP chains with those derived from human insulin and IGF-1. Each peptide was assessed in vitro for agonism and antagonism at the human insulin and the human insulin-like growth factor 1 receptor (IGF-1R). Results: We report here that one of these VILPs, lymphocystis disease virus-1 (LCDV1)-VILP, has the unique property to be a potent and full antagonist of the IGF-1R. We demonstrate the coordinated importance of the B- and C-chains of the VILP in regulating this activity. Moreover, mutation of the glycine following the first cysteine in the B-chain of IGF-1 to serine, in concert with substitution to the connecting peptide of LCDV1-VILP, converted native IGF-1 to a high potency antagonist. Conclusions: The results reveal novel aspects in ligand–receptor interactions at the IGF-1 receptor and identify a set of antagonists of potential medicinal importance.http://www.sciencedirect.com/science/article/pii/S2212877821001630InsulinInsulin-like growth factor 1IGF-1Peptide synthesisReceptor antagonismVirus-derived peptides |
| spellingShingle | Fa Zhang Emrah Altindis C. Ronald Kahn Richard D. DiMarchi Vasily Gelfanov A viral insulin-like peptide is a natural competitive antagonist of the human IGF-1 receptor Molecular Metabolism Insulin Insulin-like growth factor 1 IGF-1 Peptide synthesis Receptor antagonism Virus-derived peptides |
| title | A viral insulin-like peptide is a natural competitive antagonist of the human IGF-1 receptor |
| title_full | A viral insulin-like peptide is a natural competitive antagonist of the human IGF-1 receptor |
| title_fullStr | A viral insulin-like peptide is a natural competitive antagonist of the human IGF-1 receptor |
| title_full_unstemmed | A viral insulin-like peptide is a natural competitive antagonist of the human IGF-1 receptor |
| title_short | A viral insulin-like peptide is a natural competitive antagonist of the human IGF-1 receptor |
| title_sort | viral insulin like peptide is a natural competitive antagonist of the human igf 1 receptor |
| topic | Insulin Insulin-like growth factor 1 IGF-1 Peptide synthesis Receptor antagonism Virus-derived peptides |
| url | http://www.sciencedirect.com/science/article/pii/S2212877821001630 |
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