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Humans have been suffered from viral infections over the centuries, such as influenza, HSV, and HIV, which have killed millions of people worldwide. However, the availability of effective treatments for infectious diseases remains limited until now, as most of the viral pathogens resisted to many medical treatments. Marine microbes are currently one of the most copious sources of pharmacologically active natural products, which have constantly provided promising antivirus agents. To date, a large number of marine microbial secondary metabolites with antiviral activities have been widely reported. In this review, we have summarized the potential antivirus compounds from marine microorganisms over the last decade. In addition, the structures, bioactivities, and origins of these compounds were discussed as well., Graphical abstract Image 1, Highlights • Marine microbes-derived natural products with various antiviral activities were summarized (2009–2019). • 18 compounds demonstrated significant antivirus activities stronger than the corresponding positive drugs. • This review highlighted the potential development of these natural products as antiviral lead compounds.

Enterovirus 71 (EV71) and Coxsackievirus A16 (CVA16) are the two major causative agents of hand, foot and mouth disease (HFMD), for which there are currently no licenced treatments. Here, the acquisition of resistance towards two novel capsid-binding compounds, NLD and ALD, was studied and compared to the analogous compound GPP3. During serial passage, EV71 rapidly became resistant to each compound and mutations at residues I113 and V123 in VP1 were identified. A mutation at residue 113 was also identified in CVA16 after passage with GPP3. The mutations were associated with reduced thermostability and were rapidly lost in the absence of inhibitors. In silico modelling suggested that the mutations prevented the compounds from binding the VP1 pocket in the capsid. Although both viruses developed resistance to these potent pocket-binding compounds, the acquired mutations were associated with large fitness costs and reverted to WT phenotype and sequence rapidly in the absence of inhibitors. The most effective inhibitor, NLD, had a very large selectivity index, showing interesting pharmacological properties as a novel anti-EV71 agent., Highlights • Resistance to each compound developed rapidly, mutations at residues I113 and V123 were identified. • Resistance mutations were associated with a large fitness cost. • The mutations resulted in reduced affinity for the pocket factor. • The most effective inhibitor, NLD, had a very large therapeutic window, and has potential as a novel anti-EV71 agent.

Highlights ► Many traditional Chinese herbal medicines (TCHM) are used in China for the treatment of viral infections. ► These TCHM may contain drug-like molecules with antiviral activity. ► Novel antiviral compounds may potentially be identified in TCHM through activity-guided fractionation. ► Research on active molecules in TCHM is being aided by the development of large databases., Traditional Chinese herbal medicine (TCHM) is widely used in the prevention and treatment of viral infectious diseases. However, the operative mechanisms of TCHM remain largely obscure, mainly because of its complicated nature and the fragmented nature of research. In recent years, systematic methodologies have been developed to discover the active compounds in TCHM and to elucidate its underlying mechanisms. In this review, we summarize recent progress in TCHM-based antiviral research in China and other Asian countries. In particular, this review focuses on progress in targeting key steps in the viral replication cycle and key cellular components of the host defense system. Recent developments in centralized and standardized TCHM screening and databases are also summarized.