Drug Discovery for Snakebite Envenoming: Wanderings Amid Historical Antidotes and Emerging Therapeutic Opportunities

Snakebite envenoming is acknowledged as neglected tropical disease affecting populations of regions with limited access to healthcare systems. However, it had posed a major threat to human health since classical antiquity, when plant‐ and animal‐based remedies were extensively used as antidotes to counteract bites by venomous snakes. Although the provision of safe and effective treatments by 2030 is among the strategic objectives of the World Health Organization, clinically approved therapies currently available remain animal‐derived polyclonal antibodies, which suffer from significant limitations, including high production costs, limited cross‐species efficacy, and risk of adverse immune reactions. In this review, we survey some historical antidotes used to treat snakebite envenoming in classical antiquity and early modern Europe such as theriac, mithridatum, Orvietan and Mattioli's scorpion oil. We then discuss natural compounds that, while found also as active ingredients in medical plants used for the preparation of the historical antidotes, over the last decades have inspired research efforts aimed at characterizing their evidence‐based antivenom activity with the aim of offering potential alternatives to biologic‐based therapies. Finally, we outline emerging therapeutic opportunities that, arising from drug repurposing efforts, may pave the way for the development of novel, broadly effective therapies against multiple venomous snake species.