N-terminus Research Laboratory, Yorba Linda, CA, USA.
Department of Biochemistry, Government College University, Faisalabad, Pakistan.
J Diet Suppl. 2023;20(2):254-283. doi: 10.1080/19390211.2021.2006387. Epub 2021 Dec 1.
The emergence of fast-spreading SARS-CoV-2 mutants has sparked a new phase of COVID-19 pandemic. There is a dire necessity for antivirals targeting highly conserved genomic domains on SARS-CoV-2 that are less prone to mutation. The , also known as the (RdRp), the core component of 'SARS-CoV-2 replication-transcription complex', is a potential well-conserved druggable antiviral target. Several FDA-approved RdRp 'nucleotide analog inhibitors (NAIs)' such as remdesivir, have been repurposed to treat COVID-19 infections. The NAIs target RdRp protein translation and competitively block the nucleotide insertion into the RNA chain, resulting in the inhibition of viral replication. However, the replication proofreading function of could provide resistance to SARS-CoV-2 against many NAIs. Conversely, the 'non-nucleoside analog inhibitors (NNAIs)' bind to allosteric sites on viral polymerase surface, change the redox state; thereby, exert antiviral activity by altering interactions between the enzyme substrate and active core catalytic site of the RdRp. NNAIs neither require metabolic activation (unlike NAIs) nor compete with intracellular pool of nucleotide triphosphates (NTPs) for anti-RdRp activity. The NNAIs from phytonutrient origin are potential antiviral candidates compared to their synthetic counterparts. Several studies reported the antiviral spectrum of natural phytonutrient-NNAIs such as , (flavonolignan), (tea polyphenol), (5,6,7-trihydroxyflavone, (gallotannin), (citrus bioflavonoid), (pyrrolidine alkaloid), with superior redox characteristics (free binding energy, hydrogen-bonds, etc.) than antiviral drugs (i.e. remdesivir, favipiravir). These phytonutrient-NNAIs also exert anti-inflammatory, antioxidant, immunomodulatory and cardioprotective functions, with multifunctional therapeutic benefits in the clinical management of COVID-19.
快速传播的 SARS-CoV-2 突变株的出现引发了 COVID-19 大流行的新阶段。非常有必要针对 SARS-CoV-2 上高度保守的基因组结构域开发抗病毒药物，这些结构域不易发生突变。聚合酶（RdRp），也称为 RNA 依赖性 RNA 聚合酶（RdRp），是“SARS-CoV-2 复制-转录复合物”的核心成分，是一个具有潜力的、保守的、可成药的抗病毒靶点。几种已获 FDA 批准的 RdRp“核苷酸类似物抑制剂（NAIs）”，如瑞德西韦，已被重新用于治疗 COVID-19 感染。NAIs 靶向 RdRp 蛋白翻译，并竞争性地阻止核苷酸插入 RNA 链，从而抑制病毒复制。然而，RdRp 的复制校对功能可能会使 SARS-CoV-2 对许多 NAI 产生耐药性。相反，“非核苷酸类似物抑制剂（NNAIs）”结合病毒聚合酶表面的变构位点，改变氧化还原状态；从而通过改变酶底物与 RdRp 活性核心催化位点之间的相互作用发挥抗病毒活性。NNAIs 既不需要代谢激活（与 NAI 不同），也不需要与细胞内核苷酸三磷酸（NTP）池竞争抗 RdRp 活性。与合成类似物相比，来自植物营养素的 NNAIs 是有潜力的抗病毒候选物。几项研究报告了天然植物营养素-NNAIs 的抗病毒谱，如槲皮素、染料木素（flavonolignan）、表没食子儿茶素没食子酸酯（EGCG，tea polyphenol）、白杨素（5,6,7-三羟基黄酮）、鞣花单宁（gallotannin）、橙皮苷（citrus bioflavonoid）、胡椒碱（pyrrolidine alkaloid），它们具有比抗病毒药物（如瑞德西韦、法匹拉韦）更好的氧化还原特性（自由结合能、氢键等）。这些植物营养素-NNAIs 还具有抗炎、抗氧化、免疫调节和心脏保护作用，在 COVID-19 的临床管理中具有多功能治疗益处。
