Orphan Three-Finger Toxins from Snake Venoms: Unexplored Library of Novel Biological Ligands with Potential New Structures and Functions.

Three-finger toxins (3FTxs) from snake venom are the most abundant toxin family of mini non-enzymatic proteins, comprising 40-70% of the venom proteome. Despite their common three-finger structural scaffold, 3FTxs exhibit diverse pharmacological functions. Other than neurotoxins, they also include analgesic acid-sensing ion channel blockers, sodium and potassium channel modulators, integrin- and G-protein-coupled-receptor-targeting ligands, and gamma-aminobutyric acid type A receptor modulators that collectively span pain, cardiovascular, oncologic, and neurologic indications. However, in this fast-growing 3FTx family, there are several hundred 3FTxs whose functions have not yet been determined. Here, we systematically analyzed over 550 amino acid sequences of 3FTxs. Based on their structural features, we have classified them into more than 150 distinct subgroups. This updated information on this novel 3FTx toolkit will provide an unexplored library of investigational ligands and pharmacophores with potential therapeutic and diagnostic leads, as well as research tools. Thus, this review will provide new impetus in toxin research and pave the way for the design of potent, selective ligands for new sets of target receptors, ion channels, and enzymes.