A mini-review of the anti-SARS-CoV-2 potency of Amaryllidaceae alkaloids

Ngoc-Thao-Hien Le; Kerrin Janssen; Johannes Kirchmair; Luc Pieters; Emmy Tuenter

doi:10.1016/j.phymed.2024.155576

A mini-review of the anti-SARS-CoV-2 potency of Amaryllidaceae alkaloids

Phytomedicine. 2024 Mar 29:129:155576. doi: 10.1016/j.phymed.2024.155576. Online ahead of print.

Authors

Ngoc-Thao-Hien Le¹, Kerrin Janssen², Johannes Kirchmair³, Luc Pieters⁴, Emmy Tuenter⁵

Affiliations

¹ Natural Products & Food Research and Analysis - Pharmaceutical Technologies (NatuRAPT), Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium; Université Paris Cité - INSERM Unit 1284, Paris, France. Electronic address: NgocThaoHien.Le@uantwerpen.be.
² Department of Pharmaceutical Sciences, University of Vienna, 1090 Vienna, Austria; Institute of Physical and Theoretical Chemistry, Technische Universität Braunschweig, Gaußstraße 17, 38106 Braunschweig, Germany.
³ Department of Pharmaceutical Sciences, University of Vienna, 1090 Vienna, Austria; Christian Doppler Laboratory for Molecular Informatics in the Biosciences, Department for Pharmaceutical Sciences, University of Vienna, 1090 Vienna, Austria.
⁴ Natural Products & Food Research and Analysis - Pharmaceutical Technologies (NatuRAPT), Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.
⁵ Natural Products & Food Research and Analysis - Pharmaceutical Technologies (NatuRAPT), Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium. Electronic address: Emmy.Tuenter@uantwerpen.be.

PMID: 38579643
DOI: 10.1016/j.phymed.2024.155576

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.

Purpose and study design: 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.

Conclusion: 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.

Keywords: Amaryllidaceae alkaloids; COVID-19; Cytotoxicity; SARS-CoV-2; Structure-activity relationship.