Azadirachta indica A. Juss bark extract and its Nimbin isomers restrict β-coronaviral infection and replication

Lucky Sarkar; Lauren Oko; Soham Gupta; Andrew N Bubak; Bishnu Das; Parna Gupta; Abass Alao Safiriyu; Chirag Singhal; Ujjwal Neogi; David Bloom; Arup Banerjee; Ravi Mahalingam; Randall J Cohrs; Michael Koval; Kenneth S Shindler; Debnath Pal; Maria Nagel; Jayasri Das Sarma

doi:10.1016/j.virol.2022.01.002

Azadirachta indica A. Juss bark extract and its Nimbin isomers restrict β-coronaviral infection and replication

Virology. 2022 Apr:569:13-28. doi: 10.1016/j.virol.2022.01.002. Epub 2022 Feb 15.

Authors

Lucky Sarkar¹, Lauren Oko², Soham Gupta³, Andrew N Bubak², Bishnu Das⁴, Parna Gupta⁴, Abass Alao Safiriyu¹, Chirag Singhal¹, Ujjwal Neogi³, David Bloom⁵, Arup Banerjee⁶, Ravi Mahalingam², Randall J Cohrs², Michael Koval⁷, Kenneth S Shindler⁸, Debnath Pal⁹, Maria Nagel², Jayasri Das Sarma¹⁰

Affiliations

¹ Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, Nadia, India.
² Department of Neurology, University of Colorado School of Medicine, Aurora, CO, 80045, USA.
³ The Systems Virology Lab, Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.
⁴ Department of Chemical Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, Nadia, India.
⁵ Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, FL, USA.
⁶ Laboratory of Virology, Regional Centre for Biotechnology, and Translational Health Science & Technology Institute Faridabad, Haryana, India.
⁷ Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA.
⁸ Departments of Ophthalmology and Neurology, University of Pennsylvania, Scheie Eye Institute, Philadelphia, PA, USA.
⁹ Department of Computational and Data Sciences, Indian Institute of Science, Bangalore Karnataka, 560012, India.
¹⁰ Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, Nadia, India; Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: [email protected].

Abstract

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.

Keywords: Antiviral; Azadirachtaindica A. Juss (Neem bark extract); Beta-coronavirus; Epinimbin/Nimbin; Inhibitor of viral entry and spread; RdRp (RNA dependant RNA polymerase); SARS-CoV-2; Virus spike protein; m-CoV-MHV-A59/RSA59.

MeSH terms

Animals
Antiviral Agents / pharmacology
Azadirachta*
COVID-19 Drug Treatment*
Limonins
Mice
Plant Bark
Plant Extracts / pharmacology
SARS-CoV-2
Virus Replication

Substances

Antiviral Agents
Limonins
Plant Extracts
nimbin