The coronavirus disease 2019 (COVID-19) pandemic has been both prolonged and deadly, disrupting ordinary life and business activity to an extent unprecedented over the last hundred years. The agent responsible for this, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has shown itself largely unaffected by a host of repurposed and newly developed drugs and drug candidates.
A recent paper in the Saudi Journal of Biological Sciences seeks to open up new approaches by reviewing a list of compounds derived from plants and other natural sources, which have potential inhibitory activity against the coronavirus.
Background
Traditional medicines have proven to be very useful as a source of antiviral compounds from natural sources, which could be developed as drugs. Not only are such compounds available in plenty, but they are generally well-tolerated in therapeutic doses, are reasonably inexpensive, and belong to a range of chemical structures.
The problems inherent in identifying and validating such compounds include the high-throughput screening using accurate techniques, given the largely unknown mechanisms of action and area of activity, as well as their complex chemical structures.
Moreover, these are more likely to require much time and effort to isolate, purify, and characterize. Their sources are also relatively less easy to access.
In this review, the most effective compounds, with the lowest half-maximal inhibitory concentrations (IC50), include luteolin, saikosaponin B2, silvestrol, griffithsin and cepharanthine.
Protease inhibition
The potent anti-replicative activity shown by many of these compounds is often due to their inhibition of viral proteases that cleave the viral polyprotein to produce active compounds essential for viral replication. That is, the viral proteases are required to cleave the replicase enzymes to allow viral replication to proceed.
The replicase-encoding ribonucleic acid (RNA) is translated in the viral genome. The replicase gene encodes the proteases needed to liberate both themselves and other non-structural proteins.
Among these proteases is a papain-like protease (PLpro), essential for viral polyprotein processing and, secondly, for ubiquitin chain cleavage with subsequent inactivation of interferon-stimulated genes. This indicates that compounds that antagonize PLpro could be promising leads for antiviral drug development.
PLpro antagonists show anti-SARS-CoV activity
Modified flavonoids such as tomentins from the fruits of Paulownia tomentosa showed inhibitory activity against PLpro, required for viral replication.
Again, Lycoris radiata extract showed antiviral activity, with novel plant chemicals and a high therapeutic index. Similarly, the SARS-CoV 3CLpro was antagonized by the root extract of Isatis indigotica, as well as indigo, sinigrin, aloe emodin, and hesperetin, with sinigrin showing the greatest potency.
Amide derivatives of glycyrrhizin also showed much higher anti-coronavirus activity compared to the parent compound, but at the expense of greater toxicity. Tanshinones also inhibited SARS-CoV papain-like protease (PLpro) and 3CLpro, via inhibition of deubiquitylation.
Complement inhibition
Luteolin is a flavonoid compound present in many plant-based formulations, including Herba Artemisiae, Herba Houttuyniae, and Flos Chrysanthemi Indici. It shows a remarkable ability to antagonize complement activation via both the classical and alternative pathways, thus limiting inflammatory damage.
The role of complement in immune-mediated hyper-inflammation is important in causing systemic injury and respiratory failure in severe COVID-19, making this a promising avenue for future exploration.
Viral replication inhibition
Saikosaponins are isolated from herbs like Bupleurum spp., Heteromorpha spp., and Scrophularia scorodonia, and have been demonstrated to have antiviral activity, with a high safety margin. Of these, saikosaponin B2 inhibits early viral replication, virus-host cell attachment, and entry into the cell. It has been reported to inhibit the seasonal human coronavirus 229E (HCoV-229E).
3-beta friedelanol and other friedelanol-containing triterpenoids also show the same activity with high potency. The same activity was seen with compounds called pyranoxanthones, from the roots of Calophyllum blanco.
Lectins also appeared to act in a bi-pronged manner, first inhibiting viral attachment and the second inhibiting the final part of the infectious phase. Griffithsin is isolated from the red marine alga Griffithsia, and is a natural lectin that presents carbohydrate-binding sites. It binds to the glycan residues on the MERS-CoV spike protein, and so inhibits virus-host cell attachment.
In a mouse experiment, it reduced both symptomatic illness and the number of deaths following SARS-CoV infection, while modulating the immune response of the host cell.
Anti-MERS-CoV activity
Compounds like resveratrol and silvestrol showed anti-MERS-CoV activity, inhibiting viral replication and rescuing infected cells. When administered on consecutive doses, the effect may be sustained without reducing its inhibitory effect.
Repurposing natural compounds
Among several compounds screened for their anti-SARS-CoV-2 repurposing potential, cepharanthine, mefloquine hydrochloride, and selamectin showed remarkable inhibition of viral replication. Inhibition with cepharanthine resulted in 15,000-fold lower levels of viral replication compared to controls.
This may be accounted for by the inhibition of coronavirus entry as well as later processes occurring within the cell.
Other repurposing possibilities include niclosamide, an anthelmintic drug, which prevents SARS-CoV replication. Similarly, cinanserin is a serotonin antagonist that shows potent inhibition of viral replication with no evidence of toxicity.
Implications
The range of activity and chemical structure of natural compounds with antiviral activity, as well as the large safety margins, promote their exploration as potential antiviral drugs. Despite the difficulty of their isolation and accessibility, the spectrum of activity and efficacy means that they deserve to be explored to find potential therapeutic and/or preventive agents for this perplexing virus.
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