Potential role of Mappain, a prenylated stilbene, in reducing SARS-CoV-2 envelope protein-induced inflammation

Abstract

As of right now, more than 776 million people have contracted the COVID-19-causing SARS-CoV-2 virus, which has also resulted in over 7 million deaths. A dysregulated host's innate immune response to the virus exacerbates clinical outcomes and leads to cytokine storm. Developing a drug targeting the multiple aspects of the SARS-CoV-2 virus-host cell interactions is essential for effective treatment. The 75 amino acid-long SARS-CoV-2 envelope (2E) protein is a small structural transmembrane protein that plays a crucial role in the viral life cycle and pathogenesis. Mappain is a plant-derived stilbene from Macaranga species that previously demonstrated antiviral potential against enteroviruses in tissue culture. This study aims to assess the inhibitory potential of Mappain against SARS-CoV-2 key proteins and induced hyperinflammation using computational and in-vitro approaches. Autodock Vina was used to evaluate mappain interaction with SARS- CoV-2 antiviral targets including Spike, Envelope, Membrane, 3CLPro, PLpro, Nucleocapsid N and C termini, RdRP, and host receptors—TLR2, TLR3, TLR7, and TLR8. Afterwards, mappain was subjected to in-vitro bioassay testing using inhibition 2E-induced cytokines (IL-6 and TNF-α) in human peripheral blood mononuclear cells, measured by ELISA; Amantadine as control. KEGG pathway enrichment analysis was further performed using network pharmacology to elucidate the mechanism. Mappain demonstrated a high binding score with all the targets, especially with the envelope protein (− 9.6 kcal/mol) and TLR2 (− 9.7 kcal/mol) compared to Amantadine (− 6.1 kcal/mol and − 5.5 kcal/mol, respectively). Mappain also significantly reduced the expression of 2E-induced Interleukin 6 (p ≤ 0.001) and tumour necrosis factor-alpha (p ≤ 0.01) in the PBMCs, when compared to Amantadine HCl. The KEGG Pathway enrichment analysis supports the anti-inflammatory potential of mappain in the virus-induced cytokine storm by specifically targeting TLR signalling and COVID-19 pathways.