Design and Pharmacological Characterization of α4β1 Integrin Cyclopeptide Agonists : Computational Investigation of Ligand Determinants for Agonism versus Antagonism
α4β1 integrin is a cell adhesion receptor deeply involved in the migration and accumulation of leukocytes. Therefore, integrin antagonists that inhibit leukocytes recruitment are currently regarded as a therapeutic opportunity for the treatment of inflammatory disorder, including leukocyte-related autoimmune diseases. Recently, it has been suggested that integrin agonists capable to prevent the release of adherent leukocytes might serve as therapeutic agents as well. However, very few α4β1 integrin agonists have been discovered so far, thus precluding the investigation of their potential therapeutic efficacy. In this perspective, we synthesized cyclopeptides containing the LDV recognition motif found in the native ligand fibronectin. This approach led to the discovery of potent agonists capable to increase the adhesion of α4 integrin-expressing cells. Conformational and quantum mechanics computations predicted distinct ligand-receptor interactions for antagonists or agonists, plausibly referable to receptor inhibition or activation.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:66 |
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| Enthalten in: |
Journal of medicinal chemistry - 66(2023), 7 vom: 13. Apr., Seite 5021-5040 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Anselmi, Michele [VerfasserIn] |
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| Links: |
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| Themen: |
Integrin alpha4beta1 |
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| Anmerkungen: |
Date Completed 14.04.2023 Date Revised 07.06.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.jmedchem.2c02098 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM35481897X |
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| 100 | 1 | |a Anselmi, Michele |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Design and Pharmacological Characterization of α4β1 Integrin Cyclopeptide Agonists |b Computational Investigation of Ligand Determinants for Agonism versus Antagonism |
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| 500 | |a Date Revised 07.06.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a α4β1 integrin is a cell adhesion receptor deeply involved in the migration and accumulation of leukocytes. Therefore, integrin antagonists that inhibit leukocytes recruitment are currently regarded as a therapeutic opportunity for the treatment of inflammatory disorder, including leukocyte-related autoimmune diseases. Recently, it has been suggested that integrin agonists capable to prevent the release of adherent leukocytes might serve as therapeutic agents as well. However, very few α4β1 integrin agonists have been discovered so far, thus precluding the investigation of their potential therapeutic efficacy. In this perspective, we synthesized cyclopeptides containing the LDV recognition motif found in the native ligand fibronectin. This approach led to the discovery of potent agonists capable to increase the adhesion of α4 integrin-expressing cells. Conformational and quantum mechanics computations predicted distinct ligand-receptor interactions for antagonists or agonists, plausibly referable to receptor inhibition or activation | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Integrin alpha4beta1 |2 NLM | |
| 650 | 7 | |a Integrin beta1 |2 NLM | |
| 650 | 7 | |a Peptides, Cyclic |2 NLM | |
| 650 | 7 | |a Ligands |2 NLM | |
| 650 | 7 | |a Integrins |2 NLM | |
| 700 | 1 | |a Baiula, Monica |e verfasserin |4 aut | |
| 700 | 1 | |a Spampinato, Santi |e verfasserin |4 aut | |
| 700 | 1 | |a Artali, Roberto |e verfasserin |4 aut | |
| 700 | 1 | |a He, Tingting |e verfasserin |4 aut | |
| 700 | 1 | |a Gentilucci, Luca |e verfasserin |4 aut | |
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