TY - JOUR
T1 - A bimolecular modification strategy for developing long-lasting bone anabolic aptamer
AU - Zhang, Huarui
AU - Yu, Sifan
AU - Ni, Shuaijian
AU - Gubu, Amu
AU - Ma, Yuan
AU - Zhang, Yihao
AU - Li, Haitian
AU - Wang, Yuzhe
AU - Wang, Luyao
AU - Zhang, Zongkang
AU - Yu, Yuanyuan
AU - Lyu, Aiping
AU - Zhang, Baoting
AU - Zhang, Ge
N1 - This study was supported by the National Key R&D Program of China (2018YFA0800802), Hong Kong General Research Fund (CUHK 4108322, CUHK 14109721, CUHK 14103121, CUHK 14103420, HKBU 12100921, HKBU 12114416, HKBU 12101117, HKBU 12100918, HKBU 12101018, HKBU 12103519, HKBU 14100218, China), CUHK Direct Grant (4054714), the Young Scientists Fund of the National Natural Science Foundation of China (82304378), Theme-based Research Scheme (T12-201-20R), Interdisciplinary Research Clusters Matching Scheme of Hong Kong Baptist University (RC-IRCs/17-18/02, China), Guangdong Basic and Applied Basic Research Foundation (2019B1515120089, 2020A1515110630, China), Guangdong-Hong Kong Technology Cooperation Funding Scheme (GHP/149/21GD, 2023A0505010015), Key-Area R&D Program of Department of Science and Technology of Hunan Province (2022WK2010), and Science and Technology Innovation Commission of Shenzhen Municipality Funds (JCYJ20160229210357960, China).
Publisher Copyright:
© 2023 The Authors
PY - 2023/12/12
Y1 - 2023/12/12
N2 - 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.
AB - 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.
KW - aptamers
KW - long-lasting modification
KW - low-molecular-weight coupling agents
KW - MT: Oligonucleotides: Therapies and Applications
KW - osteogenesis imperfecta
KW - sclerostin
UR - http://www.scopus.com/inward/record.url?scp=85177815577&partnerID=8YFLogxK
U2 - 10.1016/j.omtn.2023.102073
DO - 10.1016/j.omtn.2023.102073
M3 - Journal article
AN - SCOPUS:85177815577
SN - 2162-2531
VL - 34
JO - Molecular Therapy - Nucleic Acids
JF - Molecular Therapy - Nucleic Acids
M1 - 102073
ER -