A bimolecular modification strategy for developing long-lasting bone anabolic aptamer
The molecular weight of nucleic acid aptamers (20 kDa) is lower than the cutoff threshold of the renal filtration (30–50 kDa), resulting in a very short half-life, which dramatically limits their druggability. To address this, we utilized 3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-(4-hydroxy-2-oxo-2...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-12-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253123002913 |
| _version_ | 1797454366105403392 |
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| author | Huarui Zhang Sifan Yu Shuaijian Ni Amu Gubu Yuan Ma Yihao Zhang Haitian Li Yuzhe Wang Luyao Wang Zongkang Zhang Yuanyuan Yu Aiping Lyu Baoting Zhang Ge Zhang |
| author_facet | Huarui Zhang Sifan Yu Shuaijian Ni Amu Gubu Yuan Ma Yihao Zhang Haitian Li Yuzhe Wang Luyao Wang Zongkang Zhang Yuanyuan Yu Aiping Lyu Baoting Zhang Ge Zhang |
| author_sort | Huarui Zhang |
| collection | DOAJ |
| description | The molecular weight of nucleic acid aptamers (20 kDa) is lower than the cutoff threshold of the renal filtration (30–50 kDa), resulting in a very short half-life, which dramatically limits their druggability. To address this, we utilized 3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-(4-hydroxy-2-oxo-2H-chromen-6-yl)propenamide (HC) and 12-((2,5-dioxopyrrolidin-1-yl)oxy)-12-oxododecanoic acid (DA), two newly designed coupling agents, for synergistic binding to human serum albumin (HSA). Both HC and DA are conjugated to a bone anabolic aptamer (Apc001) against sclerostin to form an Apc001OC conjugate with high binding affinity to HSA. Notably, HC and DA could synergistically facilitate prolonging the half-life of the conjugated Apc001 and promoting its bone anabolic potential. Using the designed blocking peptides, the mechanism studies indicate that the synergistic effect of HC-DA on pharmacokinetics and bone anabolic potential of the conjugated Apc001 is achieved via their synergistic binding to HSA. Moreover, biweekly Apc001OC at 50 mg/kg shows comparable bone anabolic potential to the marketed sclerostin antibody given weekly at 25 mg/kg. This proposed bimolecular modification strategy could help address the druggability challenge for aptamers with a short half-life. |
| first_indexed | 2024-03-09T15:36:11Z |
| format | Article |
| id | doaj.art-9411b16d164745c69a52c4f392875295 |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-03-09T15:36:11Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-9411b16d164745c69a52c4f3928752952023-11-26T05:12:21ZengElsevierMolecular Therapy: Nucleic Acids2162-25312023-12-0134102073A bimolecular modification strategy for developing long-lasting bone anabolic aptamerHuarui Zhang0Sifan Yu1Shuaijian Ni2Amu Gubu3Yuan Ma4Yihao Zhang5Haitian Li6Yuzhe Wang7Luyao Wang8Zongkang Zhang9Yuanyuan Yu10Aiping Lyu11Baoting Zhang12Ge Zhang13School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, ChinaSchool of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China; Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China; Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery, Hong Kong SAR, China; Corresponding author: Sifan Yu, School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, ChinaLaw Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, Hong Kong Baptist University, Hong Kong SAR, ChinaLaw Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, Hong Kong Baptist University, Hong Kong SAR, ChinaSchool of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, ChinaLaw Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, Hong Kong Baptist University, Hong Kong SAR, ChinaThe Second Clinical Medical School, Henan University of Chinese Medicine, Zhengzhou, ChinaLaw Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, Hong Kong Baptist University, Hong Kong SAR, ChinaSchool of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, ChinaLaw Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, Hong Kong Baptist University, Hong Kong SAR, ChinaLaw Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, Hong Kong Baptist University, Hong Kong SAR, ChinaSchool of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China; Corresponding author: Baoting Zhang, School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, Hong Kong Baptist University, Hong Kong SAR, China; Corresponding author: Ge Zhang, Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, Hong Kong Baptist University, Hong Kong SAR, China.The molecular weight of nucleic acid aptamers (20 kDa) is lower than the cutoff threshold of the renal filtration (30–50 kDa), resulting in a very short half-life, which dramatically limits their druggability. To address this, we utilized 3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-(4-hydroxy-2-oxo-2H-chromen-6-yl)propenamide (HC) and 12-((2,5-dioxopyrrolidin-1-yl)oxy)-12-oxododecanoic acid (DA), two newly designed coupling agents, for synergistic binding to human serum albumin (HSA). Both HC and DA are conjugated to a bone anabolic aptamer (Apc001) against sclerostin to form an Apc001OC conjugate with high binding affinity to HSA. Notably, HC and DA could synergistically facilitate prolonging the half-life of the conjugated Apc001 and promoting its bone anabolic potential. Using the designed blocking peptides, the mechanism studies indicate that the synergistic effect of HC-DA on pharmacokinetics and bone anabolic potential of the conjugated Apc001 is achieved via their synergistic binding to HSA. Moreover, biweekly Apc001OC at 50 mg/kg shows comparable bone anabolic potential to the marketed sclerostin antibody given weekly at 25 mg/kg. This proposed bimolecular modification strategy could help address the druggability challenge for aptamers with a short half-life.http://www.sciencedirect.com/science/article/pii/S2162253123002913MT: Oligonucleotides: Therapies and Applicationsaptamerslong-lasting modificationsclerostinosteogenesis imperfectalow-molecular-weight coupling agents |
| spellingShingle | Huarui Zhang Sifan Yu Shuaijian Ni Amu Gubu Yuan Ma Yihao Zhang Haitian Li Yuzhe Wang Luyao Wang Zongkang Zhang Yuanyuan Yu Aiping Lyu Baoting Zhang Ge Zhang A bimolecular modification strategy for developing long-lasting bone anabolic aptamer Molecular Therapy: Nucleic Acids MT: Oligonucleotides: Therapies and Applications aptamers long-lasting modification sclerostin osteogenesis imperfecta low-molecular-weight coupling agents |
| title | A bimolecular modification strategy for developing long-lasting bone anabolic aptamer |
| title_full | A bimolecular modification strategy for developing long-lasting bone anabolic aptamer |
| title_fullStr | A bimolecular modification strategy for developing long-lasting bone anabolic aptamer |
| title_full_unstemmed | A bimolecular modification strategy for developing long-lasting bone anabolic aptamer |
| title_short | A bimolecular modification strategy for developing long-lasting bone anabolic aptamer |
| title_sort | bimolecular modification strategy for developing long lasting bone anabolic aptamer |
| topic | MT: Oligonucleotides: Therapies and Applications aptamers long-lasting modification sclerostin osteogenesis imperfecta low-molecular-weight coupling agents |
| url | http://www.sciencedirect.com/science/article/pii/S2162253123002913 |
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