Design of chimeric GLP-1A using oligomeric bile acids to utilize transporter-mediated endocytosis for oral delivery
Abstract Background Despite the effectiveness of glucagon-like peptide-1 agonist (GLP-1A) in the treatment of diabetes, its large molecular weight and high hydrophilicity result in poor cellular permeability, thus limiting its oral bioavailability. To address this, we developed a chimeric GLP-1A tha...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Association for the Advancement of Science (AAAS)
2023-09-01
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| Series: | Biomaterials Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40824-023-00421-7 |
| _version_ | 1827331190219079680 |
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| author | Seho Kweon Jun-Hyuck Lee Seong-Bin Yang Seong Jin Park Laxman Subedi Jung-Hyun Shim Seung-Sik Cho Jeong Uk Choi Youngro Byun Jooho Park Jin Woo Park |
| author_facet | Seho Kweon Jun-Hyuck Lee Seong-Bin Yang Seong Jin Park Laxman Subedi Jung-Hyun Shim Seung-Sik Cho Jeong Uk Choi Youngro Byun Jooho Park Jin Woo Park |
| author_sort | Seho Kweon |
| collection | DOAJ |
| description | Abstract Background Despite the effectiveness of glucagon-like peptide-1 agonist (GLP-1A) in the treatment of diabetes, its large molecular weight and high hydrophilicity result in poor cellular permeability, thus limiting its oral bioavailability. To address this, we developed a chimeric GLP-1A that targets transporter-mediated endocytosis to enhance cellular permeability to GLP-1A by utilizing the transporters available in the intestine, particularly the apical sodium-dependent bile acid transporter (ASBT). Methods In silico molecular docking and molecular dynamics simulations were used to investigate the binding interactions of mono-, bis-, and tetra-deoxycholic acid (DOCA) (monoDOCA, bisDOCA, and tetraDOCA) with ASBT. After synthesizing the chimeric GLP-1A-conjugated oligomeric DOCAs (mD-G1A, bD-G1A, and tD-G1A) using a maleimide reaction, in vitro cellular permeability and insulinotropic effects were assessed. Furthermore, in vivo oral absorption in rats and hypoglycemic effect on diabetic db/db mice model were evaluated. Results In silico results showed that tetraDOCA had the lowest interaction energy, indicating high binding affinity to ASBT. Insulinotropic effects of GLP-1A-conjugated oligomeric DOCAs were not different from those of GLP-1A-Cys or exenatide. Moreover, bD-G1A and tD-G1A exhibited improved in vitro Caco-2 cellular permeability and showed higher in vivo bioavailability (7.58% and 8.63%) after oral administration. Regarding hypoglycemic effects on db/db mice, tD-G1A (50 μg/kg) lowered the glucose level more than bD-G1A (50 μg/kg) compared with the control (35.5% vs. 26.4%). Conclusion GLP-1A was conjugated with oligomeric DOCAs, and the resulting chimeric compound showed the potential not only for glucagon-like peptide-1 receptor agonist activity but also for oral delivery. These findings suggest that oligomeric DOCAs can be used as effective carriers for oral delivery of GLP-1A, offering a promising solution for enhancing its oral bioavailability and improving diabetes treatment. Graphical Abstract |
| first_indexed | 2024-03-07T16:31:33Z |
| format | Article |
| id | doaj.art-698d5645b1db4894abda682df979998c |
| institution | Directory Open Access Journal |
| issn | 2055-7124 |
| language | English |
| last_indexed | 2024-03-07T16:31:33Z |
| publishDate | 2023-09-01 |
| publisher | American Association for the Advancement of Science (AAAS) |
| record_format | Article |
| series | Biomaterials Research |
| spelling | doaj.art-698d5645b1db4894abda682df979998c2024-03-03T10:32:17ZengAmerican Association for the Advancement of Science (AAAS)Biomaterials Research2055-71242023-09-0127111810.1186/s40824-023-00421-7Design of chimeric GLP-1A using oligomeric bile acids to utilize transporter-mediated endocytosis for oral deliverySeho Kweon0Jun-Hyuck Lee1Seong-Bin Yang2Seong Jin Park3Laxman Subedi4Jung-Hyun Shim5Seung-Sik Cho6Jeong Uk Choi7Youngro Byun8Jooho Park9Jin Woo Park10Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, Seoul National UniversityDepartment of Applied Life Science, Graduate School, BK21 Program, Konkuk UniversityDepartment of Applied Life Science, Graduate School, BK21 Program, Konkuk UniversityCollege of Pharmacy, Seoul National UniversityBiomedicine Cutting Edge Formulation Technology Center, Mokpo National UniversityBiomedicine Cutting Edge Formulation Technology Center, Mokpo National UniversityDepartment of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Biomedical and Healthcare Research Institute, Mokpo National UniversityCollege of Pharmacy, Research Institute of Pharmaceutical Sciences, Chonnam National UniversityCollege of Pharmacy, Seoul National UniversityDepartment of Applied Life Science, Graduate School, BK21 Program, Konkuk UniversityBiomedicine Cutting Edge Formulation Technology Center, Mokpo National UniversityAbstract Background Despite the effectiveness of glucagon-like peptide-1 agonist (GLP-1A) in the treatment of diabetes, its large molecular weight and high hydrophilicity result in poor cellular permeability, thus limiting its oral bioavailability. To address this, we developed a chimeric GLP-1A that targets transporter-mediated endocytosis to enhance cellular permeability to GLP-1A by utilizing the transporters available in the intestine, particularly the apical sodium-dependent bile acid transporter (ASBT). Methods In silico molecular docking and molecular dynamics simulations were used to investigate the binding interactions of mono-, bis-, and tetra-deoxycholic acid (DOCA) (monoDOCA, bisDOCA, and tetraDOCA) with ASBT. After synthesizing the chimeric GLP-1A-conjugated oligomeric DOCAs (mD-G1A, bD-G1A, and tD-G1A) using a maleimide reaction, in vitro cellular permeability and insulinotropic effects were assessed. Furthermore, in vivo oral absorption in rats and hypoglycemic effect on diabetic db/db mice model were evaluated. Results In silico results showed that tetraDOCA had the lowest interaction energy, indicating high binding affinity to ASBT. Insulinotropic effects of GLP-1A-conjugated oligomeric DOCAs were not different from those of GLP-1A-Cys or exenatide. Moreover, bD-G1A and tD-G1A exhibited improved in vitro Caco-2 cellular permeability and showed higher in vivo bioavailability (7.58% and 8.63%) after oral administration. Regarding hypoglycemic effects on db/db mice, tD-G1A (50 μg/kg) lowered the glucose level more than bD-G1A (50 μg/kg) compared with the control (35.5% vs. 26.4%). Conclusion GLP-1A was conjugated with oligomeric DOCAs, and the resulting chimeric compound showed the potential not only for glucagon-like peptide-1 receptor agonist activity but also for oral delivery. These findings suggest that oligomeric DOCAs can be used as effective carriers for oral delivery of GLP-1A, offering a promising solution for enhancing its oral bioavailability and improving diabetes treatment. Graphical Abstracthttps://doi.org/10.1186/s40824-023-00421-7Chimeric peptideOral GLP-1 agonistOligomeric bile acidsIn silico molecular dockingASBT-mediated endocytosis |
| spellingShingle | Seho Kweon Jun-Hyuck Lee Seong-Bin Yang Seong Jin Park Laxman Subedi Jung-Hyun Shim Seung-Sik Cho Jeong Uk Choi Youngro Byun Jooho Park Jin Woo Park Design of chimeric GLP-1A using oligomeric bile acids to utilize transporter-mediated endocytosis for oral delivery Biomaterials Research Chimeric peptide Oral GLP-1 agonist Oligomeric bile acids In silico molecular docking ASBT-mediated endocytosis |
| title | Design of chimeric GLP-1A using oligomeric bile acids to utilize transporter-mediated endocytosis for oral delivery |
| title_full | Design of chimeric GLP-1A using oligomeric bile acids to utilize transporter-mediated endocytosis for oral delivery |
| title_fullStr | Design of chimeric GLP-1A using oligomeric bile acids to utilize transporter-mediated endocytosis for oral delivery |
| title_full_unstemmed | Design of chimeric GLP-1A using oligomeric bile acids to utilize transporter-mediated endocytosis for oral delivery |
| title_short | Design of chimeric GLP-1A using oligomeric bile acids to utilize transporter-mediated endocytosis for oral delivery |
| title_sort | design of chimeric glp 1a using oligomeric bile acids to utilize transporter mediated endocytosis for oral delivery |
| topic | Chimeric peptide Oral GLP-1 agonist Oligomeric bile acids In silico molecular docking ASBT-mediated endocytosis |
| url | https://doi.org/10.1186/s40824-023-00421-7 |
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