The Inhibition of RNA Viruses by Amaryllidaceae Alkaloids: Opportunities for the Development of Broad‐Spectrum Anti‐Coronavirus Drugs

Abstract

The global COVID‐19 pandemic has claimed the lives of millions and disrupted nearly every aspect of human society. Currently, vaccines remain the only widely available medical means to address the cause of the pandemic, the SARS‐CoV‐2 virus. Unfortunately, current scientific consensus deems the emergence of vaccine‐resistant SARS‐CoV‐2 variants highly likely. In this context, the design and development of broad‐spectrum, small‐molecule based antiviral drugs has been described as a potentially effective, alternative medical strategy to address circulating and re‐emerging CoVs. Small molecules are well‐suited to target the least‐rapidly evolving structures within CoVs such as highly conserved RNA replication enzymes, and this renders them less vulnerable to evolved drug resistance. Examination of the vast literature describing the inhibition of RNA viruses by Amaryllidaceae alkaloids suggests that future, broad‐spectrum anti‐CoV drugs may be derived from this family of natural products.

Truncated ring-A amaryllidaceae alkaloid modulates the host cell integrated stress response, exhibiting antiviral activity to HSV-1 and SARSCoV-2

“…These results turned our focus to the ring-A substituents as the last remaining fragment available for modification. All analogs investigated for RNA viral activity possess the 8,9-methylenedioxy substituent fused to ring-A 22 . Only one prior study has investigated alternative ring-A hydroxyl positionings.…”

“…The ability to activate innate antiviral immunity through type I and/or III interferon stimulation has been described for small molecule lipids such as bile acids 40 , retinoids 41 , and the topical antiviral agent imiquimod 42 , involving complex regulatory pathways. Prior to this work, the contribution of the ring-A oxy-substituents of narciclasine-type alkaloids to antiviral activity was unknown 22 . While the ability of this class of alkaloid to inhibit protein biosynthesis at the ribosomal level was known, the target and mechanism was not clear 22 .…”

“…Current approved and investigational therapeutics are either repurposed or designed agents that target key viral proteins such as protease or RNA polymerase inhibition 4 . Alkaloids isolated from various members of the amaryllidaceae plant family 5 have wide pharmacological potential in view of the anticancer 6 – 16 , antiviral 17 – 22 and acetylcholinesterase activities they have demonstrated. The antiviral activity of narciclasine ( 1 ) and a wide range of alkaloids (Fig.…”

“…The mechanism of action responsible for the spectrum of antiviral activity observed in the narciclasine class is not clear. Inhibition of protein biosynthesis through interaction with human eukaryotic translation elongation factor 1A (eEF1A) has been previously implicated and recently reviewed 22 . The broad-spectrum activity against not only DNA, but also against RNA viruses is intriguing and may imply the activation of a host-defense mechanism rather than a specific viral target.…”

Chemical Synthesis and Biological Activities of Amaryllidaceae Alkaloid Norbelladine Derivatives and Precursors

“…The development of antiviral therapeutics based on AAs may provide decisive medical solutions to catastrophic pandemics. Since many of these molecules exert their antiviral action by targeting host factors, they present opportunities to develop broad-spectrum treatments that are less susceptible to the emergence of drug resistance [ 24 ].…”