article · Scientific Reports
The ongoing emergence of drug-resistant influenza strains necessitates the discovery of alternative therapeutic options. In this study, plant-derived indole and beta-carboline alkaloids were screened for antiviral properties against both human seasonal influenza A H1N1 and avian influenza A H5N1 strains. In cell-based tests, compounds including strychnine sulfate, harmalol, harmane, and harmaline demonstrated notable inhibitory effects against the viruses, matching or exceeding the performance of standard control drugs such as zanamivir and amantadine. Plaque reduction assays confirmed substantial viral suppression at non-toxic dosage levels. Investigation into the mechanisms showed differing modes of action: harmane and harmalol primarily disrupted viral replication, harmaline exerted direct viricidal effects, and strychnine sulfate hindered viral attachment to host cells. Computational analyses revealed that hydrogen bonding via the indole moiety is key to these interactions, with harmalol displaying favourable lipophilicity and efficiency metrics.
Influenza viruses continually evolve resistance to standard antiviral medications, creating a persistent threat to global public health. Identifying active plant-derived compounds with distinct modes of action provides new candidate molecules for drug development, offering potential alternative strategies to counteract seasonal and avian influenza infections.
This research is at an early laboratory stage, demonstrating in vitro efficacy and computational binding characteristics in cell cultures. It could inform pharmaceutical developers and antiviral drug discovery programmes seeking candidate lead molecules or scaffolds targeting drug-resistant influenza strains. Substantial further preclinical testing, formulation development, and safety optimisation would be required before therapeutic applications can be realised.
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Abstract The persistent evolution of drug-resistant influenza strains represents a global concern. The innovation of new treatment approaches through drug screening strategies and investigating the antiviral potential of bioactive natural-based chemicals may address the issue. Herein, we screened the anti-influenza efficacy of some biologically active indole and β-carboline (βC) indole alkaloids against two different influenza A viruses (IAV) with varied host range ranges; seasonal influenza A/Egypt/NRC098/2019(H1N1) and avian influenza A/chicken/Egypt/N12640A/2016(H5N1). All compounds were first assessed for their half-maximal cytotoxic concentration (CC 50 ) in MDCK cells and half-maximal inhibitory concentrations (IC 50 ) against influenza A/H5N1. Intriguingly, Strychnine sulfate, Harmalol, Harmane, and Harmaline showed robust anti-H5N1 activities with IC 50 values of 11.85, 0.02, 0.023, and 3.42 µg/ml, respectively, as compared to zanamivir and amantadine as control drugs (IC 50 = 0.079 µg/ml and 17.59 µg/ml, respectively). The efficacy of the predefined phytochemicals was further confirmed against influenza A/H1N1 and they displayed potent anti-H1N1 activities compared to reference drugs. Based on SI values, the highly promising compounds were then evaluated for antiviral efficacy through plaque reduction assay and consistently they revealed high viral inhibition percentages at non-toxic concentrations. By studying the modes of antiviral action, Harmane and Harmalol could suppress viral infection via interfering mainly with the viral replication of the influenza A/H5N1 virus, whilst Harmaline exhibited a viricidal effect against the influenza A/H5N1 virus. Whereas, Strychnine sulfate elucidated its anti-influenza potency by interfering with viral adsorption into MDCK cells. Consistently, chemoinformatic studies showed that all studied phytochemicals illustrated HB formations with essential peptide cleft through the NH of indole moiety. Among active alkaloids, harmalol displayed the best lipophilicity metrics including ligand efficiency (LE) and ligand lipophilic efficiency (LLE) for both viruses. Compounds geometry and their ability to participate in HB formation are very crucial.
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DOI: 10.1038/s41598-023-27954-0
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