Drug Development Gets Dangerous

It has been an unusually hot summer. Vast swathes of the globe have tumor masses. This innovative approach has been successfully tested in experienced prolonged heatwaves and jellyfish, bees, wasps, scorpions, snakes and spiders have thrived in the balmy temperatures. All of these creatures have varieties that are able to produce venom, deployed via a deliverymechanism (such as a sting, barb or fang) to catch prey and/or act as a defense mechanism. Although usually painful rather than fatal to humans, venomous species still account for more than 80,000 deaths annually. Indeed, a recent envenoming study reported by The Lancet on July 12, 2018, predicted that 90% of the global population live within range of areas inhabited by snakes, and 272.91 million individuals are exposed to venomous snakes where no effective therapy exists. Venoms typically comprise a complex mix of biochemicals that are evolutionarily adapted to interact with a variety of cellular components within the target organism. Someof these active compoundshaveexquisitelypotent and selective modes of action that have the potential to be coopted formedicinal use. In fact the termpharmacology is derived from the ancient Greek pharmakon, meaning remedy and poison, and this dichotomy between the harmful and beneficial actions of venom has fascinated mankind for millennia. Although the surge in bites and stings this summer has been largely unwelcome, researchers who dedicate their time to understanding venom have used it as an opportunity to gathermore samples. Venomics describes the study of venom and its toxicological profiles via the integration of – omics technologies. As high-throughput techniques have improved, so too has the ability to separate and identify peptides and enzymes of interest within a heterogeneous venom often containing more than 1000 components. The purification of individualmolecules, followed by their functional interrogation using relevant assays, has enabled the identification of numerous novel therapeutic leads. Sterile blister packs and tablet bottles often belie the exotic origin of their active ingredients. The first venomderived drug that entered general medical use was captopril, which was granted US Food and Drug Administration (FDA) approval in 1981. Based on a peptide found in the venom of a species of lancehead viper, captopril was shown tobe an extremely effective angiotensin-converting enzyme inhibitor. Thanks to its vasodilatory properties, captopril was marketed as a treatment for hypertension and congestive heart failure, and its huge commercial success fueled the quest to develop new venom-inspired drugs. The currentnumberof venom-inspiredUSFDA-approveddrugs in common use is rather modest (~6), although the drug development pipeline is healthy as attested by themany spin-out companies trying to commercialize promising compounds. One such example is Blaze Bioscience, founded by Jim Olson, a neuro-oncologist at the Fred Hutchinson Cancer Research Center (Seattle, USA). While screening venom from the death stalker scorpion, one of the peptides, chlorotoxin, was found to bindwith high affinity to cancerous cells whilst sparing non-malignant cells. This preferential binding was due to chlorotoxin’s affinity to matrix metalloprotease MMP2 subtypes that are upregulated on the surface of certain cancers. By conjugating chlorotoxin to a fluorescent dye (BLZ-100, tozuleristide), Olson devised a Tumor Paint that could be used by surgeons to aid resection of