That applicability soon arrived when it was found that the reprolysins were part of a protease subgroup called “a disintegrin and metalloproteinase with thrombospondin motifs.” The multidomain ADAMTS proteases were generating quite a bit of research interest, since many of them were implicated in inflammation, atherosclerosis and cancer.
Since then, Fox and his lab have spent a lot of time in cancer research (although he still makes time for numerous side projects and collaborations in toxinology), particularly examining how cells, the surrounding extracellular matrix and proteases interact in promoting the invasion and metastasis of cancer cells. He’s shown, for example, that melanoma cells can influence the gene expression of nearby fibroblasts in the stromal tissue to produce a more invasion-friendly microenvironment.
“Of course, our studies are just one example of a significant element regarding the repertoire of proteins in snake and other venoms,” Fox says. “Namely that nearly all venom peptides identified to date have human orthologs. The venomous versions are just slightly modified to give them a pronounced effect.”
And that pronounced effect has led to significant payoffs both in research, where venom biology has led the way to understanding the role of certain proteins in mammals, and in medicine, as more than 20 venom-derived drugs and diagnostics have been approved or are in development.
Fox believes that these drugs represent just a fraction of venom’s potential in biomedicine. “I consider venoms to be great natural products libraries (the venom of a single snake can contain up to 50 different proteins and peptides) that probably still hide many secrets,” he says. “We know most of the protein components by now, but what isn’t known is the overall activity profile.”
Once identified, venom peptides usually are assayed for a single, pre-defined toxic activity, whether it’s blocking an ion channel or inducing blood coagulation.
To this end, Fox also has become involved in using proteomic approaches to look into the functionality of venom peptides, such as analyzing post-translational modifications or proteolytic processing. He believes that by using such emerging technologies, researchers can uncover new activities in venom, and that will lead to new drugs.
JBC highlight: Serrano, S. M. T., Kim, J., Wang, D., Dragulev, B., Shannon, J. D., Mann, H. H., Veit, G., Wagener, R., Koch, M., and Fox, J. W. (2006) The cysteine-rich domain of snake venom metalloproteinases is a ligand for von Willebrand factor A domains: role in substrate targeting. J. Biol. Chem. 281, 39746 – 39756.