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Design of chimeric GLP-1A using oligomeric bile acids to utilize transporter-mediated endocytosis for oral delivery
DC Field | Value | Language |
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dc.contributor.author | Kweon, Seho | - |
dc.contributor.author | Lee, Jun-Hyuck | - |
dc.contributor.author | Yang, Seong-Bin | - |
dc.contributor.author | Park, Seong Jin | - |
dc.contributor.author | Subedi, Laxman | - |
dc.contributor.author | Shim, Jung-Hyun | - |
dc.contributor.author | Cho, Seung-Sik | - |
dc.contributor.author | Choi, Jeong Uk | - |
dc.contributor.author | Byun, Youngro | - |
dc.contributor.author | Park, Jooho | - |
dc.contributor.author | Park, Jin Woo | - |
dc.date.accessioned | 2023-09-14T05:37:41Z | - |
dc.date.available | 2023-09-14T14:38:12Z | - |
dc.date.issued | 2023-09-02 | - |
dc.identifier.citation | Biomaterials Research, Vol.27(1):83 | ko_KR |
dc.identifier.issn | 2055-7124 | - |
dc.identifier.uri | https://hdl.handle.net/10371/195548 | - |
dc.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. | ko_KR |
dc.description.sponsorship | This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (grant nos. 2020R1A2C1102831, 2022R1A5A8033794, 2022R1A4A3034038). This study was also supported by Regional Innovation Strategy (RIS) through the NRF funded by the Ministry of Education (MOE) (2021RIS-001) | ko_KR |
dc.language.iso | en | ko_KR |
dc.publisher | BMC | ko_KR |
dc.subject | Chimeric peptide | - |
dc.subject | Oral GLP-1 agonist | - |
dc.subject | Oligomeric bile acids | - |
dc.subject | In silico molecular docking | - |
dc.subject | ASBT-mediated endocytosis | - |
dc.title | Design of chimeric GLP-1A using oligomeric bile acids to utilize transporter-mediated endocytosis for oral delivery | ko_KR |
dc.type | Article | ko_KR |
dc.identifier.doi | 10.1186/s40824-023-00421-7 | ko_KR |
dc.citation.journaltitle | Biomaterials Research | ko_KR |
dc.language.rfc3066 | en | - |
dc.rights.holder | The Korean Society for Biomaterials | - |
dc.date.updated | 2023-09-03T03:08:45Z | - |
dc.citation.volume | 27 | ko_KR |
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