Shearer Victoria, Yu Chen-Hsu, Han Xuan, Sczepanski Jonathan T
Department of Chemistry, Texas A&M University College Station Texas 77843 USA
Chem Sci. 2024 Oct 21;15(44):18239-58. doi: 10.1039/d4sc05157b.
Chemically modified nucleotides are central to the development of biostable research tools and oligonucleotide therapeutics. In this context, l-oligonucleotides, the synthetic enantiomer of native d-nucleic acids, hold great promise. As enantiomers, l-oligonucleotides share the same physical and chemical properties as their native counterparts, yet their inverted l-(deoxy)ribose sugars afford them orthogonality towards the stereospecific environment of biology. Notably, l-oligonucleotides are highly resistant to degradation by cellular nucleases, providing them with superior biostability. As a result, l-oligonucleotides are being increasingly utilized for the development of diverse biomedical technologies, including molecular imaging tools, diagnostic biosensors, and aptamer-based therapeutics. Herein, we present recent such examples that highlight the clinical potential of l-oligonucleotides. Additionally, we provide our perspective on the remaining challenges and practical considerations currently associated with the use of l-oligonucleotides and explore potential solutions that will lead to the broader adoption of l-oligonucleotides in clinical applications.
化学修饰的核苷酸是生物稳定研究工具和寡核苷酸疗法发展的核心。在这种背景下，L-寡核苷酸作为天然D-核酸的合成对映体，具有巨大的潜力。作为对映体，L-寡核苷酸与其天然对应物具有相同的物理和化学性质，但其倒置的L-（脱氧）核糖糖使其在生物学的立体特异性环境中具有正交性。值得注意的是，L-寡核苷酸对细胞核酸酶的降解具有高度抗性，赋予它们卓越的生物稳定性。因此，L-寡核苷酸正越来越多地用于多种生物医学技术的开发，包括分子成像工具、诊断生物传感器和基于适体的疗法。在此，我们展示了最近的此类实例，突出了L-寡核苷酸的临床潜力。此外，我们阐述了目前与使用L-寡核苷酸相关的剩余挑战和实际考量，并探索了可能促成L-寡核苷酸在临床应用中更广泛采用的潜在解决方案。
