Abstract：
BACKGROUND: Nature has perennially served as an infinite reservoir of diverse chemicals with numerous applications benefiting humankind. In recent years, due to the emerging COVID-19 pandemic, there has been a surge in studies on repurposing natural products as anti-SARS-CoV-2 agents, including plant-derived substances. Among all types of natural products, alkaloids remain one of the most important groups with various known medicinal values. The current investigation focuses on Amaryllidaceae alkaloids (AAs) since AAs have drawn significant scientific attention as anti-SARS-CoV-2 agents over the past few years.
OBJECTIVE: This study serves as a mini-review, summarizing recent advances in studying the anti-SARS-CoV-2 potency of AAs, covering two aspects: structure-activity relationship and mechanism of action (MOA).
METHODS: The study covers the period from 2019 to 2023. The information in this review were retrieved from common databases including Web of Science, ScienceDirect, PubMed and Google scholar. Reported anti-SARS-CoV-2 potency, cytotoxicity and possible biological targets of AAs were summarized and classified into different skeletal subclasses. Then, the structure-activity relationship (SAR) was explored, pinpointing the key pharmacophore-related structural moieties. To study the mechanism of action of anti-SARS-CoV-2 AAs, possible biological targets were discussed.
RESULTS: In total, fourteen research articles about anti-SARS-CoV-2 was selected. From the SAR point of view, four skeletal subclasses of AAs (lycorine-, galanthamine-, crinine- and homolycorine-types) appear to be promising for further investigation as anti-SARS-CoV-2 agents despite experimental inconsistencies in determining in vitro half maximal inhibitory effective concentration (EC50). Narciclasine, haemanthamine- and montanine-type skeletons were cytotoxic and devoid of anti-SARS-CoV-2 activity. The lycorine-type scaffold was the most structurally diverse in this study and preliminary structure-activity relationships revealed the crucial role of ring C and substituents on rings A, C and D in its anti-SARS-CoV-2 activity. It also appears that two enantiomeric skeletons (haemanthamine- and crinine-types) displayed opposite activity/toxicity profiles regarding anti-SARS-CoV-2 activity. Pharmacophore-related moieties of the haemanthamine/crinine-type skeletons were the substituents on rings B, C and the dioxymethylene moiety. All galanthamine-type alkaloids in this study were devoid of cytotoxicity and it appears that varying substituents on rings C and D could enhance the anti-SARS-CoV-2 potency. Regarding MOAs, initial experimental results suggested Mpro and RdRp as possible viral targets. Dual functionality between anti-inflammatory activity on host cells and anti-SARS-CoV-2 activity on the SARS-CoV-2 virus of isoquinoline alkaloids, including AAs, were suggested as the possible MOAs to alleviate severe complications in COVID-19 patients. This dual functionality was proposed to be related to the p38 MAPK signaling pathway.
CONCLUSIONS: Overall, Amaryllidaceae alkaloids appear to be promising for further investigation as anti-SARS-CoV-2 agents. The skeletal subclasses holding the premise for further investigation are lycorine-, crinine-, galanthamine- and homolycorine-types.
OBJECTIVE: This study serves as a mini-review, summarizing recent advances in studying the anti-SARS-CoV-2 potency of AAs, covering two aspects: structure-activity relationship and mechanism of action (MOA).
METHODS: The study covers the period from 2019 to 2023. The information in this review were retrieved from common databases including Web of Science, ScienceDirect, PubMed and Google scholar. Reported anti-SARS-CoV-2 potency, cytotoxicity and possible biological targets of AAs were summarized and classified into different skeletal subclasses. Then, the structure-activity relationship (SAR) was explored, pinpointing the key pharmacophore-related structural moieties. To study the mechanism of action of anti-SARS-CoV-2 AAs, possible biological targets were discussed.
RESULTS: In total, fourteen research articles about anti-SARS-CoV-2 was selected. From the SAR point of view, four skeletal subclasses of AAs (lycorine-, galanthamine-, crinine- and homolycorine-types) appear to be promising for further investigation as anti-SARS-CoV-2 agents despite experimental inconsistencies in determining in vitro half maximal inhibitory effective concentration (EC50). Narciclasine, haemanthamine- and montanine-type skeletons were cytotoxic and devoid of anti-SARS-CoV-2 activity. The lycorine-type scaffold was the most structurally diverse in this study and preliminary structure-activity relationships revealed the crucial role of ring C and substituents on rings A, C and D in its anti-SARS-CoV-2 activity. It also appears that two enantiomeric skeletons (haemanthamine- and crinine-types) displayed opposite activity/toxicity profiles regarding anti-SARS-CoV-2 activity. Pharmacophore-related moieties of the haemanthamine/crinine-type skeletons were the substituents on rings B, C and the dioxymethylene moiety. All galanthamine-type alkaloids in this study were devoid of cytotoxicity and it appears that varying substituents on rings C and D could enhance the anti-SARS-CoV-2 potency. Regarding MOAs, initial experimental results suggested Mpro and RdRp as possible viral targets. Dual functionality between anti-inflammatory activity on host cells and anti-SARS-CoV-2 activity on the SARS-CoV-2 virus of isoquinoline alkaloids, including AAs, were suggested as the possible MOAs to alleviate severe complications in COVID-19 patients. This dual functionality was proposed to be related to the p38 MAPK signaling pathway.
CONCLUSIONS: Overall, Amaryllidaceae alkaloids appear to be promising for further investigation as anti-SARS-CoV-2 agents. The skeletal subclasses holding the premise for further investigation are lycorine-, crinine-, galanthamine- and homolycorine-types.
摘要：
背景：自然界一直是各种化学物质的无限储库，具有许多有益于人类的应用。近年来,由于新出现的COVID-19大流行，关于将天然产物重新用作抗SARS-CoV-2药物的研究激增，包括植物来源的物质。在所有类型的天然产品中，生物碱仍然是具有各种已知药用价值的最重要的群体之一。当前的调查集中在石豆科生物碱（AAs）上，因为在过去的几年中，AAs作为抗SARS-CoV-2药物引起了广泛的科学关注。
目的：本研究是一个小型综述，总结了AAs抗SARS-CoV-2效力研究的最新进展，涵盖两个方面：构效关系和作用机制（MOA）。
方法：该研究涵盖了2019年至2023年的时期。这篇综述中的信息是从包括WebofScience在内的公共数据库中检索的，ScienceDirect,PubMed和谷歌学者。报告的抗SARS-CoV-2效力，总结了AAs的细胞毒性和可能的生物学靶标，并将其分为不同的骨骼亚类。然后，探索了结构-活性关系(SAR)，精确定位关键的药效团相关结构部分。为了研究抗SARS-CoV-2AAs的作用机制，讨论了可能的生物学目标。
结果：总计，选择了14篇关于抗SARS-CoV-2的研究文章。从SAR的角度来看,AAs的四个骨骼亚类(lycorine-，加兰他胺-,尽管在确定体外半数最大抑制有效浓度（EC50）方面存在实验不一致，但Crinine和homolycorine类型）似乎有望作为抗SARS-CoV-2药物进行进一步研究。Narciclasine,血胺和montanine型骨骼具有细胞毒性，并且没有抗SARS-CoV-2活性。在这项研究中，石蒜碱类型的支架是结构上最多样化的，初步的结构-活性关系揭示了环C和环A上的取代基的关键作用，C和D的抗SARS-CoV-2活性。似乎两种对映体骨架（血胺和黄嘌呤类型）在抗SARS-CoV-2活性方面表现出相反的活性/毒性特征。血原胺/crinine型骨架的药效基团相关部分是B环上的取代基，C和二甲醛部分。这项研究中的所有加兰他敏型生物碱都没有细胞毒性，并且似乎环C和D上的不同取代基可以增强抗SARS-CoV-2的效力。关于MOA，初步实验结果表明Mpro和RdRp可能是病毒靶标。异喹啉生物碱对宿主细胞的抗炎活性和对SARS-CoV-2病毒的抗SARS-CoV-2活性之间的双重功能，包括AA，被认为是减轻COVID-19患者严重并发症的可能方法。这种双重功能被认为与p38MAPK信号通路有关。
结论：总体而言，石豆科生物碱似乎有望作为抗SARS-CoV-2药物进行进一步研究。持有进一步调查前提的骨骼亚类是石蒜碱-，Crinine-,加兰他胺和同型。
目的：本研究是一个小型综述，总结了AAs抗SARS-CoV-2效力研究的最新进展，涵盖两个方面：构效关系和作用机制（MOA）。
方法：该研究涵盖了2019年至2023年的时期。这篇综述中的信息是从包括WebofScience在内的公共数据库中检索的，ScienceDirect,PubMed和谷歌学者。报告的抗SARS-CoV-2效力，总结了AAs的细胞毒性和可能的生物学靶标，并将其分为不同的骨骼亚类。然后，探索了结构-活性关系(SAR)，精确定位关键的药效团相关结构部分。为了研究抗SARS-CoV-2AAs的作用机制，讨论了可能的生物学目标。
结果：总计，选择了14篇关于抗SARS-CoV-2的研究文章。从SAR的角度来看,AAs的四个骨骼亚类(lycorine-，加兰他胺-,尽管在确定体外半数最大抑制有效浓度（EC50）方面存在实验不一致，但Crinine和homolycorine类型）似乎有望作为抗SARS-CoV-2药物进行进一步研究。Narciclasine,血胺和montanine型骨骼具有细胞毒性，并且没有抗SARS-CoV-2活性。在这项研究中，石蒜碱类型的支架是结构上最多样化的，初步的结构-活性关系揭示了环C和环A上的取代基的关键作用，C和D的抗SARS-CoV-2活性。似乎两种对映体骨架（血胺和黄嘌呤类型）在抗SARS-CoV-2活性方面表现出相反的活性/毒性特征。血原胺/crinine型骨架的药效基团相关部分是B环上的取代基，C和二甲醛部分。这项研究中的所有加兰他敏型生物碱都没有细胞毒性，并且似乎环C和D上的不同取代基可以增强抗SARS-CoV-2的效力。关于MOA，初步实验结果表明Mpro和RdRp可能是病毒靶标。异喹啉生物碱对宿主细胞的抗炎活性和对SARS-CoV-2病毒的抗SARS-CoV-2活性之间的双重功能，包括AA，被认为是减轻COVID-19患者严重并发症的可能方法。这种双重功能被认为与p38MAPK信号通路有关。
结论：总体而言，石豆科生物碱似乎有望作为抗SARS-CoV-2药物进行进一步研究。持有进一步调查前提的骨骼亚类是石蒜碱-，Crinine-,加兰他胺和同型。
