Marine Sponge and Sponge-Associated Fungal Metabolites as Emerging Antiviral Scaffolds

Abstract

The urgent need for novel antiviral therapeutics, driven by emerging viral threats and the limitations of current treatment options, has prompted a systematic investigation into marine natural products. This systematic review evaluates the potential of secondary metabolites derived from marine sponges and sponge-associated fungi as emerging pipelines for antiviral drug discovery. Sponge-derived compounds, including nucleoside analogues and bromotyrosines, primarily inhibit viral polymerases and entry mechanisms, whereas sponge-associated fungal metabolites, such as xanthones and meroterpenoids, exhibit broader chemical diversity and more varied mechanistic profiles, including multitarget inhibition and fusion disruption. Ecological analyses indicate that marine sponges function as holobionts under intense microbial pressure, driving the evolution of chemically distinct secondary metabolites. Quantitative potency data demonstrate that several microbial metabolites achieve antiviral activity in the low micromolar range, with selectivity indices exceeding 13 for certain compounds. Structural features recurrently associated with broad-spectrum activity include polyoxygenated scaffolds, halogenation, and rigid polycyclic systems. However, critical translational gaps persist: no quantitative head-to-head comparative studies between sponge-associated and free-living fungal metabolites exist, and current in vitro screening models fail to capture pharmacokinetics or host toxicity. Machine learning approaches remain underrepresented in this domain. We conclude that sponge-associated fungi represent a richer source of unusual antiviral chemistry than free-living counterparts, yet the evidence base remains concentrated in preclinical screening without clinical validation. Addressing these gaps through advanced preclinical models and systematic comparative studies is essential to advance these scaffolds toward therapeutic development.