Dowerah Dikshita, V N Uppuladinne Mallikarjunachari, Sarma Plaban J, Biswakarma Nishant, Sonavane Uddhavesh B, Joshi Rajendra R, Ray Suvendra K, Namsa Nima D, Deka Ramesh Ch
CMML-Catalysis and Molecular Modelling Lab, Department of Chemical Sciences, Tezpur University, Napaam, Sonitpur, Assam 784 028, India.
HPC-Medical & Bioinformatics Applications Group, Centre for Development of Advanced Computing (C-DAC), Panchavati, Pashan, Pune 411008, India.
ACS Omega. 2023 Jun 12;8(25):22382-22405. doi: 10.1021/acsomega.2c07860. eCollection 2023 Jun 27.
Antisense therapeutics treat a wide spectrum of diseases, many of which cannot be addressed with the current drug technologies. In the quest to design better antisense oligonucleotide drugs, we propose five novel LNA analogues (A1-A5) for modifying antisense oligonucleotides and establishing each with the five standard nucleic acids: adenine (A), guanine (G), cytosine (C), thymine (T), and uracil (U). Monomer nucleotides of these modifications were considered for a detailed Density Functional Theory (DFT)-based quantum chemical analysis to determine their molecular-level structural and electronic properties. A detailed MD simulation study was done on a 14-mer ASO (5'-CTTAGCACTGGCCT-3') containing these modifications targeting PTEN mRNA. Results from both molecular- and oligomer-level analysis clearly depicted LNA-level stability of the modifications, the ASO/RNA duplexes maintaining stable base pairing preferring RNA-mimicking duplexes. Notably, monomer MO isosurfaces for both purines and pyrimidines were majorly distributed on the nucleobase region in modifications A1 and A2 and in the bridging unit in modifications A3, A4, and A5, suggesting that A3/RNA, A4/RNA, and A5/RNA duplexes interact more with the RNase H and solvent environment. Accordingly, solvation of A3/RNA, A4/RNA, and A5/RNA duplexes was higher compared to that of LNA/RNA, A1/RNA, and A2/RNA duplexes. This study has resulted in a successful archetype for creating advantageous nucleic acid modifications tailored for particular needs, fulfilling a useful purpose of designing novel antisense modifications, which may overcome the drawbacks and improve the pharmacokinetics of existing LNA antisense modifications.
反义疗法可治疗多种疾病，其中许多疾病无法用当前的药物技术治疗。在致力于设计更好的反义寡核苷酸药物的过程中，我们提出了五种新型锁核酸（LNA）类似物（A1 - A5），用于修饰反义寡核苷酸，并将其与五种标准核酸：腺嘌呤（A）、鸟嘌呤（G）、胞嘧啶（C）、胸腺嘧啶（T）和尿嘧啶（U）分别组合。对这些修饰的单体核苷酸进行了基于密度泛函理论（DFT）的详细量子化学分析，以确定其分子水平的结构和电子性质。对一条含有这些修饰、靶向PTEN mRNA的14聚体反义寡核苷酸（5'-CTTAGCACTGGCCT-3'）进行了详细的分子动力学（MD）模拟研究。分子水平和寡聚体水平分析的结果清楚地描绘了这些修饰在LNA水平的稳定性，反义寡核苷酸/RNA双链体保持稳定的碱基配对，更倾向于类似RNA的双链体。值得注意的是，嘌呤和嘧啶的单体分子轨道等势面主要分布在修饰A1和A2的核碱基区域以及修饰A3、A4和A5的桥连单元中，这表明A3/RNA、A4/RNA和A5/RNA双链体与核糖核酸酶H和溶剂环境的相互作用更强。因此，与LNA/RNA、A1/RNA和A2/RNA双链体相比，A3/RNA、A4/RNA和A5/RNA双链体的溶剂化程度更高。这项研究成功创建了一个原型，用于设计满足特定需求的有利核酸修饰，实现了设计新型反义修饰的有用目的，这可能克服现有LNA反义修饰的缺点并改善其药代动力学。
