Zakaria Mohamed Y, Elmaaty Ayman Abo, El-Shesheny Rabeh, Alnajjar Radwan, Kutkat Omnia, Ben Moussa Sana, Abdullah Alzahrani Abdullah Yahya, El-Zahaby Sally A, Al-Karmalawy Ahmed A
Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, King Salman International University Ras Sudr 46612 South Sinai Egypt
Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Port Said University Port Said 42526 Egypt.
RSC Adv. 2024 Dec 9;14(52):38778-38795. doi: 10.1039/d4ra07316a. eCollection 2024 Dec 3.
There is merit in investigating novel therapeutic molecules that hit vital targets during the viral infection cycle disrupting the interaction between SARS-CoV-2's spike glycoprotein and the host's angiotensin converting enzyme 2 (ACE2) receptor, potentially offering new avenues for treatment. Accordingly, lipid-based vesicular systems like liposomes or niosomes are frequently utilized to overcome these hurdles. Thus, chemically synthesized compounds were encapsulated within PEGylated bilosomes (PBs) to improve their solubility and intestinal permeability, thereby enhancing their anti-SARS-CoV-2 effectiveness. The formulae were prepared according to 2 full factorial design which was also used to explore the impact of the change in predetermined formulation variables on the properties of the prepared vesicles (entrapment efficiency EE%, particle size PS, and zeta potential ZP). Additionally, the optimized formula (F4) which is composed of 3% bile salt (BS), 40 mg 1,2-distearoyl--glycero-3-phosphoethanolamine--[amino(polyethylene glycol)-2000] (DSPE) and sodium deoxycholate (SDC) as a bile salt, was selected as an optimum formula with desirability value 0.674 using Design Expert® software. Both the release and experiments results confirmed the significant superiority of the F4 over the drug dispersion. Both cytotoxicity and anti-SARS-CoV-2 activity of all examined compound-loaded PBs (PB3a-PB3g) were assessed in Vero E6 cells MTT assay. Both compounds PB3c and PB3g displayed the highest IC values (0.71 and 1.25 μg mL, respectively) ensuring their superior antiviral potential. Moreover, it was revealed that PB3c demonstrated more than 80% virucidal activity and over 80% inhibition of viral adsorption with little effect on the viral replication ∼(5-10%). Moreover, molecular docking and dynamic studies were conducted to pursue the binding affinities of the investigated compounds towards the ACE2 target of the SARS-CoV-2 spike protein, assuring their feasible inhibitory potential. Collectively, the investigated compound-loaded PBs can be treated as promising lead drug delivery panels for COVID-19 management.
研究在病毒感染周期中作用于关键靶点的新型治疗分子具有重要意义，这些分子可破坏严重急性呼吸综合征冠状病毒2（SARS-CoV-2）刺突糖蛋白与宿主血管紧张素转换酶2（ACE2）受体之间的相互作用，有望提供新的治疗途径。因此，脂质体或非离子型脂质体等基于脂质的囊泡系统经常被用于克服这些障碍。因此，将化学合成的化合物包裹在聚乙二醇化双分子层脂质体（PBs）中，以提高其溶解度和肠道通透性，从而增强其抗SARS-CoV-2的有效性。根据二因素全因子设计制备配方，该设计还用于探究预定配方变量的变化对所制备囊泡性质（包封率EE%、粒径PS和zeta电位ZP）的影响。此外，使用Design Expert®软件选择由3%胆盐（BS）、40 mg 二硬脂酰-sn-甘油-3-磷酸乙醇胺-[氨基（聚乙二醇）-2000]（DSPE）和脱氧胆酸钠（SDC）作为胆盐组成的优化配方（F4）作为最佳配方，可取性值为0.674。释放实验和实验结果均证实F4相对于药物分散体具有显著优势。在Vero E6细胞中通过MTT法评估了所有检测的载有化合物的PBs（PB3a-PB3g）的细胞毒性和抗SARS-CoV-2活性。化合物PB3c和PB3g均表现出最高的半数抑制浓度值（分别为0.71和1.25 μg/mL），确保了它们卓越的抗病毒潜力。此外，研究表明PB3c表现出超过80%的杀病毒活性和超过80%的病毒吸附抑制率，对病毒复制的影响很小（约5-10%）。此外，进行了分子对接和动力学研究，以探究所研究化合物与SARS-CoV-2刺突蛋白ACE2靶点之间的结合亲和力，确保它们具有可行的抑制潜力。总体而言，所研究的载有化合物的PBs可被视为用于管理2019冠状病毒病的有前景的先导药物递送载体。
