Abstract
The emergence of highly infectious pathogens with their potential for triggering global pandemics necessitate the development of effective treatment strategies, including broad-spectrum antiviral therapies to safeguard human health. This study investigates the antiviral activity of emetine, dehydroemetine (DHE), and congeneric compounds against SARS-CoV-2 and HCoV-OC43, and evaluates their impact on the host cell. Concurrently, we assess the potential cardiotoxicity of these ipecac alkaloids. Significantly, our data reveal that emetine and the (-)-R,S isomer of 2,3-dehydroemetine (designated in this paper as DHE4) reduce viral growth at nanomolar concentrations (i.e., IC 50 ~ 50–100 nM), paralleling those required for inhibition of protein synthesis, while calcium channel blocking activity occurs at elevated concentrations (i.e., IC 50 ~ 40–60 µM). Our findings suggest that the antiviral mechanisms primarily involve disruption of host cell protein synthesis and is demonstrably stereoiso-mer specific. The prospect of a therapeutic window in which emetine or DHE4 inhibit viral propagation without cardiotoxicity renders these alkaloids viable candidates in strategies worthy of clinical investigation. Abbreviations: ADME, absorption distribution metabolism and excretion; CD, circular dichroism; CMV, cytomegalovirus; COVID, coronavirus disease; CHX, cycloheximide; DHE, racemic mixture of dehydroemetines; DHE1, dehydroemetine isomer 1; DHE2, dehydroemetine isomer 2; DHE3, dehydroemetine isomer 3; DHE4, dehydroemetine isomer 4 also known as (-) 2,3 dehydroemetine; EKG, electrocardiogram; hbi, hours before infection; hpi, hours post infection; GP, Guinea pig; RdRp, an active complex of SARS-CoV-2 RNA-dependent RNA polymerase; RPS14, ribosomal protein S14; HPLC, high performance liquid chromatography; MERS, Middle East Respiratory Syndrome; MS, mass spectrometry; MTS, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazo-lium; NMR, nuclear magnetic resonance; SAR, structure-activity relationship; SARS-CoV and SARS-CoV-2, severe acute respiratory syndrome coronavirus and severe acute respiratory syndrome coronavirus-2; SI, selectivity index; SRB, sulforhodamine B; TCA, trichloroacetic acid; TGI, total growth inhibition.