Amaryllidaceae alkaloid (AAs) biosynthesis has garnered significant attention in recent years, particularly with the commercialisation of galanthamine as a treatment for the symptoms of Alzheimer\'s disease. A significant amount of research work over the last 8 decades has focused on the understanding of AA biosynthesis, starting from early radiolabelling studies to recent multi-omics analysis with modern biotechnological advancements. Those studies enabled the identification of hundreds of metabolites, the characterisation of biochemical pathway, an understanding of the environmental stimuli, and of the molecular regulation of these pharmaceutically and agriculturally important metabolites. Despite the numerous works there remain significant gaps in understanding their biosynthesis in Amaryllidaceae plants. As such, further research is needed to fully elucidate the metabolic pathway and facilitate their production. This review aims to provide a comprehensive overall summary of the current state of knowledge on AAs biosynthesis, from elicitation of transcription factors expression in the cell nucleus to alkaloid transport in the apoplast, and to highlight the challenges that need to be overcome for further advancement.

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.

Covering: 2017 to 2023 (now)Amaryllidaceae alkaloids (AAs) are a unique class of specialized metabolites containing heterocyclic nitrogen bridging that play a distinct role in higher plants. Irrespective of their diverse structures, most AAs are biosynthesized via intramolecular oxidative coupling. The complex organization of biosynthetic pathways is constantly enlightened by new insights owing to the advancement of natural product chemistry, synthetic organic chemistry, biochemistry, systems and synthetic biology tools and applications. These promote novel compound identification, trace-level metabolite quantification, synthesis, and characterization of enzymes engaged in AA catalysis, enabling the recognition of biosynthetic pathways. A complete understanding of the pathway benefits biotechnological applications in the long run. This review emphasizes the structural diversity of the AA specialized metabolites involved in biogenesis although the process is not entirely defined yet. Moreover, this work underscores the pivotal role of synthetic and enantioselective studies in justifying biosynthetic conclusions. Their prospective candidacy as lead constituents for antiviral drug discovery has also been established. However, a complete understanding of the pathway requires further interdisciplinary efforts in which antiviral studies address the structure-activity relationship. This review presents current knowledge on the topic.

BACKGROUND: Multiorgan dysfunction, especially sepsis-related multiorgan damage, remains a major cause of high mortality in the late stages of infection and a great clinical challenge. In recent years, natural drugs have received widespread attention because of their low cost, wide sources, high efficacy, low toxicity, and limited side effects. Lycorine, a natural compound extracted from Amaryllidaceae, exhibits multiple pharmacological activities, including in the regulation of autophagy and the induction of cancer cell apoptosis, and has anti-inflammatory, antifungal, antiviral, antimalarial, and antitumor activities. However, studies on lycorine have mainly focused on its antitumor properties, and research on its use for organ protection, especially in sepsis-related organ injury, is relatively limited.
OBJECTIVE: To review and discuss the effects and mechanisms of lycorine in the treatment of multi-organ dysfunction, especially sepsis.
METHODS: Literature searches in electronic databases, such as Web of Science, Science Direct, PubMed, Google Scholar, and Scopus, were performed using \'Lycorine\', \'Amaryllidaceae\', \'Pharmacology\', \'Pharmacokinetics\', \'Anti-inflammation\', \'Autophagy\', \'Apoptosis\', \'Anti-microbial and anti-parasitic\', \'Antitumor\', \'Organ protection\', and \'Sepsis\' as keywords, the correlated literature was extracted and conducted from the databases mentioned above.
RESULTS: By summarizing the progress made in existing research, we found that the general effects of lycorine involve the regulation of autophagy and the induction of cancer cell apoptosis, and anti-inflammatory, antifungal, antiviral, antimalarial, and antitumor effects; through these pathways, the compound can ameliorate organ damage. In addition, lycorine was found to have an important effect on organ damage in sepsis.
CONCLUSIONS: Lycorine is a promising natural organ protective agent. This review will provide a new theoretical basis for the treatment of organ protection, especially in sepsis.

Amaryllidaceae is a family that includes 75 genera and about 1100 species, which have a long history of medicinal use. Many plants have been proven to possess efficacy for neurological injury and inflammatory conditions. This article summarizes 357 Amaryllidaceae alkaloids, and cites 166 174 references over the last three decades. These alkaloids are classified into 14 skeleton types, and their abundant sources are also included. Modern pharmacology studies demonstrate that alkaloids that exclusively occur in Amaryllidaceae plant possess wide-ranging pharmacological actions, especially effects on the central nervous system, as well as antitumor, antimicrobial, and anti-inflammatory activities. Effective monomeric compounds from Amaryllidaceae screened for pharmacological activity in vivo and in vitro are also summarized.

The plant family Amaryllidaceae is known for its horticultural and ornamental appeal as well as its medicinal value. In relation to these characteristics, trade in Amaryllid flower varieties (especially daffodils) is a multi-million dollar revenue generator for the floriculture industry. Of greater significance are the medicinal attributes of the family, which has already spawned the Alzheimer\'s prescription drug galanthamine, a potent and selective inhibitor of the enzyme acetylcholinesterase, of significance in the progression of neurodegeneration associated with motor neuron diseases, with annual global sales of around $150 million. Furthermore, it is anticipated that an anticancer drug target related to the Amaryllidaceae alkaloid pancratistatin, presently under advanced clinical evaluation, will enter commercial circulation within the next decade. Members of the Amaryllidaceae are distributed through both tropical and subtropical regions of the globe, but are of prominence within three distinct geographical locations, including Andean South America, the Mediterranean basin, and southern Africa. The southern African zone is known to harbor at least a third of the worldwide complement of around 1000 species, many of which are widely utilized in the traditional medicinal practices of the indigenous people of the region. Given its therapeutic and economic value, its natural abundance in the southern African region, coupled to its widespread usage in ethnic medicine, the family Amaryllidaceae provides a diverse and accessible platform for phytochemical based drug discovery. A consolidation of its traditional usage as well as its chemical and pharmacological profiles will thus guide efforts aimed at maximizing this potential. In undertaking this survey of the Amaryllidaceae of southern African, we aimed to achieve these goals.

Irritancy of daffodil flowers and bulbs was assessed using various fresh plant preparations, solvent extracts and some of the known Amaryllidaceae alkaloids on guinea pigs. Sensitization was also carried out on guinea pigs using these plant preparations, solvent extracts and 7 fractions obtained after preparative chromatography of the bulb ether extract. Only 1 fraction, containing 2 alkaloids, was capable of inducing delayed hypersensitivity in the animals; the sensitivity achieved, however, was weak. The substances were identified as masonin and homolycorin, which acted as elicitors, but masonin may also be a sensitizer. While homolycorin is a known daffodil constituent, masonin has not been found previously in Narcissus pseudonarcissus. 3 other alkaloids as well as chelidonic acid and isorhamnetin were non-elicitors in the sensitized guinea pigs.