Phytochemicals Nimbin And Epinimbin From Bark Of Neem Tree are able to inhibit the SARS-CoV-2

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A new research led by scientists from the University of Colorado School of Medicine-USA and the Indian Institute of Science Education and Research Kolkata-India has found that the phytochemical compounds extracted from the bark of the neem tree (Azadirachta indica), namely the triterpenoids Nimbin And Epinimbin and its various isomers are able to inhibit the SARS-CoV-2 virus and its various variants.

The study findings were published in the peer reviewed journal: Virology (Science Direct by Elsevier) https://www.sciencedirect.com/science/article/pii/S0042682222000022

Emerging mutations in the SARS-CoV-2 genome pose a challenge for vaccine development and antiviral therapy. The antiviral efficacy of Azadirachta indica bark extract (NBE) was assessed against SARS-CoV-2 and m-CoV-RSA59 infection.

Effects of in vivo intranasal or oral NBE administration on viral load, inflammatory response, and histopathological changes were assessed in m-CoV-RSA59-infection. NBE administered inhibits SARS-CoV-2 and m-CoV-RSA59 infection and replication in vitro, reducing Envelope and Nucleocapsid gene expression.

NBE ameliorates neuroinflammation and hepatitis in vivo by restricting viral replication and spread.

Isolated fractions of NBE enriched in Nimbin isomers shows potent inhibition of m-CoV-RSA59 infection in vitro. In silico studies revealed that NBE could target Spike and RdRp of m-CoV and SARS-CoV-2 with high affinity.

NBE has a triterpenoids origin that may allow them to competitively target panoply of viral proteins to inhibit mouse and different strains of human coronavirus infections, suggesting its potential as an antiviral against pan-β-Coronaviruses.

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COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), created a worldwide crisis (Yang et al., 2020; Zhou et al., 2020). Recurrent outbreaks of SARS-CoV-2 and other human Coronaviruses (HCoVs), and the potential for new HCoVs to emerge, make finding pan-coronavirus antiviral therapies critical (Tay et al., 2020; Wang et al., 2020). While antibodies (Jiang et al., 2020), repur- posed drugs (Hossein-Khannazer et al., 2020), anti-convalescent plasma therapy (Muecksch et al., 2021), and advances in diagnosis and vaccine development (Padron-Regalado, 2020) helped manage this pandemic

(Rabaan et al., 2020), no single antiviral drug has shown pan-anti-coronaviral activity irrespective of zoonotic potential and host
targets. Understanding Coronaviruses’ properties, including genomic control of pathogenesis, host cell entry, and cell-to-cell fusion may guide new therapeutic efforts (Lu et al., 2020; V’Kovski et al., 2021).
Mechanistic studies of SARS-CoV-2 pathogenesis are difficult in patients, and experimental animal models of HCoVs are limited in mimicking human disease. Related murine-β-Coronaviruses (m-β-CoVs) facilitate studying conserved mechanisms of COVID pathobiology.
MHV-1 produces a SARS-CoV-like lethal disease (De Albuquerque et al., 2006; Hua et al., 2018), and neurotropic m-CoV-MHV-A59 or its spike protein targeted recombinant strain RSA59 infection inC57BL/6 mice initiates a biphasic disorder from acute meningoencephalomyelitis to chronic demyelination (Chakravarty and Das Sarma, 2021; Das Sarma, 2010, 2014). The consequences of SARS-CoV-2 neuro-infection as re- ported may be inferred from m-CoV-RSA59-induced neuro-COVID (Chakravarty and Das Sarma, 2021; Mao et al., 2020).

m-CoV-MHV Spike glycoprotein is a major determinant of viral entry, virus-host interaction, infection-initiation, viral antigen spread, and consecutive pathogenesis. MHV Spike protein can initiate viral entry, fusion and subsequent pathogenesis without the CEACAM1 receptor, due to immune activation (Sadasivan et al., 2017; Singh et al., 2019).

Replacement of a single amino acid in the Spike fusion domain alters pathology (Singh et al., 2019). Fusion depends on conformational transition of the six-helix bundle viral fusion core driven by hydrophobic interactions between Heptad repeats HR1 and HR2 of the S2 domain (Hoffmann et al., 2020), providing a target for mimetic peptide design. Thus, identifying anti-fusogenic properties of bark extract of the eth- nomedicinal plant Azadirachta indica A. Juss (Neem) may reveal novel therapeutics.

Neem bark extract (NBE) restricts viral-host attachment, cell-to-cell fusion, viral spread, viral replication, and viral-induced demyelination induced by m-CoV-RSA59 (Sarkar et al., 2020). NBE also inhibits Herpes simplex virus type-1 glycoprotein mediated cell-to-cell fusion and pol- ykaryocyte formation (Tiwari et al., 2010). Moreover, NBE blocks in vitro virus-free cell-to-cell fusion induced by cells expressing the m-CoV-MHV-A59 spike glycoprotein (Sarkar et al., 2020).

Viral Membrane (M), Envelope (E), and RNA-dependant RNA polymerase (RdRp) proteins also contribute to infectivity (Harrison et al., 2020) and may be affected by NBE. NBE boosts host immunity and metabolism (Alzohairy, 2016). Its antibacterial, anti-inflammatory, anti-cancer, anti-allergic, anti-parasitic, and antifungal activities support repurposing of this drug to combat COVID-19 (Lim et al., 2021).

In silico studies suggest that Neem components Nimbolin-A, Nimocin, and Cycloartanols can bind to SARS-CoV-2 E and M proteins resulting in inhibition of their function (Borkotoky and Banerjee, 2020). Desace- tylgedunin (DCG), a limonoid, bindstoSARS-CoV-2 papain-like protease (PLpro) (Baildya et al., 2021), and Azadirachtin, Nimbolinin, Nimbolide, Quercetin, and β-sitosterol have therapeutic benefits in pulmonary fibrosis and inflammation models (Prashanth Goud, Bale, Pulivendala and Godugu, 2019; Thota et al., 2020).

Here, we have tested the efficacy of NBE against SARS-CoV-2 infection in Vero E6 and A549-ACE2 cells, and effects of NBE adminis- tered intranasally or orally in m-CoV-RSA59-infectedC57BL/6 mice.

Dichloromethane fractionation of NBE and in silico studies identified key Nimbin isomers that bind to Spike proteins of m-CoV-MHV-RSA59 and SARS-CoV-2. These data advance our understanding of COVID biology and support using NBE as a pan-CoV antiviral therapy.

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