{"title":"Developing Stapled Aptamers with a Constrained Conformation for Osteogenesis Imperfect Therapeutics.","authors":"Gubu Amu, Ge Zhang, Nannan Jing, Yuan Ma","doi":"10.1021/acs.jmedchem.4c01293","DOIUrl":null,"url":null,"abstract":"<p><p>Despite the extensive development of aptamers in basic research, only a limited number have successfully progressed to clinical trials. This limitation is primarily attributed to the inherent instability of aptamers' conformation, resulting in low affinity, poor serum stability, and inconsistent potency, posing a significant challenge to their stabilization. Herein, we established a feasible strategy to develop staple aptamers using the predicted binding conformations and titration cross-linking (TTC) method. Through this strategy, we successfully synthesized various stapled sclerostin aptamers with over 70% yield. Importantly, we demonstrated that stapled aptamers significantly enhanced their affinity (approximately 20-fold) and serum stability (negligible degradation within 32 h). Moreover, in an osteogenesis imperfecta mouse model (<i>Col1a2</i><sup><i>+/G610C</i></sup> mice), the stapled aptamer (named c-0127OA) exhibited a potent antagonistic effect on sclerostin, leading to enhanced anabolic bone anabolic potential. Collectively, our established stapling strategy is effective in stabilizing aptamers' conformation, with c-0127OA emerging as a promising therapeutic candidate for osteogenesis imperfecta.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8000,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1021/acs.jmedchem.4c01293","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
Abstract
Despite the extensive development of aptamers in basic research, only a limited number have successfully progressed to clinical trials. This limitation is primarily attributed to the inherent instability of aptamers' conformation, resulting in low affinity, poor serum stability, and inconsistent potency, posing a significant challenge to their stabilization. Herein, we established a feasible strategy to develop staple aptamers using the predicted binding conformations and titration cross-linking (TTC) method. Through this strategy, we successfully synthesized various stapled sclerostin aptamers with over 70% yield. Importantly, we demonstrated that stapled aptamers significantly enhanced their affinity (approximately 20-fold) and serum stability (negligible degradation within 32 h). Moreover, in an osteogenesis imperfecta mouse model (Col1a2+/G610C mice), the stapled aptamer (named c-0127OA) exhibited a potent antagonistic effect on sclerostin, leading to enhanced anabolic bone anabolic potential. Collectively, our established stapling strategy is effective in stabilizing aptamers' conformation, with c-0127OA emerging as a promising therapeutic candidate for osteogenesis imperfecta.
期刊介绍:
The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents.
The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.