Prajapati Jignesh, Patel Rohit, Rao Priyashi, Saraf Meenu, Rawal Rakesh, Goswami Dweipayan
Department of Biochemistry & Forensic Science, University School of Sciences, Gujarat University, Ahmedabad, 380009 Gujarat India.
Department of Microbiology & Biotechnology, University School of Sciences, Gujarat University, Ahmedabad, 380009 Gujarat India.
Struct Chem. 2022;33(5):1619-1643. doi: 10.1007/s11224-022-01932-0. Epub 2022 Apr 8.
Coronavirus disease 2019 (COVID-19) persists and shook the global population where the endgame to this pandemic is brought on by developing vaccines in record-breaking time. Nevertheless, these vaccines are far from perfect where their efficiency ranges from 65 to 90%; therefore, vaccines are not the one only solution to overcome this situation, and apart from administration of vaccines, the scientific community is at quest for finding alternative solutions to incumber SARS-CoV-2 infection. In this study, our research group is keen on identifying a bioactive molecule that is independent in its mode of action from existing vaccines which can potentially target the SARS-CoV-2 virus replicative efficacy. Papain-like protease (PLpro) and main protease (Mpro) are the most lucrative targets of COVIDs against which the drugs can be developed, as these proteases play a vital role in the replication and development of viral particles. Researchers have modelled a compound such as GRL0617 and X77 as an inhibitor of Mpro and PLpro, respectively, but use of these compounds has several limitations on hosts like toxicity and solubility. Under the current study by deploying rigorous computational assessments, pool of microbial secondary metabolites was screened and handpicked to search a structural or functional analogue of GRL0617 and X77, with an idea to identify a compound that can serve as dual inhibitor for both PLpro and Mpro. From the manually curated database of known antiviral compounds from fungal origin, we found cytonic acids A and B to potentially serve as dual inhibitor of PLpro and Mpro.
2019冠状病毒病(COVID-19)持续存在并震撼了全球人口,而这场大流行的最终结局是通过在创纪录的时间内研发疫苗来实现的。然而,这些疫苗远非完美,其有效性范围在65%至90%之间;因此,疫苗并非克服这种情况的唯一解决方案,除了接种疫苗外,科学界还在寻求其他替代解决方案来抑制严重急性呼吸综合征冠状病毒2(SARS-CoV-2)感染。在本研究中,我们的研究小组热衷于鉴定一种生物活性分子,其作用方式独立于现有疫苗,可能靶向SARS-CoV-2病毒的复制效力。木瓜蛋白酶样蛋白酶(PLpro)和主要蛋白酶(Mpro)是新冠病毒最具吸引力的靶点,可针对这些靶点开发药物,因为这些蛋白酶在病毒颗粒的复制和发育中起着至关重要的作用。研究人员分别模拟了化合物GRL0617和X77作为Mpro和PLpro的抑制剂,但这些化合物的使用在宿主方面存在若干局限性,如毒性和溶解性。在当前的研究中,通过进行严格的计算评估,对微生物次级代谢产物库进行了筛选和挑选,以寻找GRL0617和X77的结构或功能类似物,目的是鉴定一种可作为PLpro和Mpro双重抑制剂的化合物。从人工整理的真菌来源已知抗病毒化合物数据库中,我们发现细胞酸A和B可能作为PLpro和Mpro的双重抑制剂。