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Written by Sarah Wornow ‘23 Edited by Geat Ramush ‘23 Researchers have been building a molecular biology manipulation toolbox for decades. From genome editing to epigenetic control, scientists have the ability to modify intracellular processes. Proteomic editing, or the editing of protein function and regulation, is one tool we don’t yet have at our disposal. However, new technology that takes advantage of proteases has recently been developed that opens the door to proteomic editing. Proteases are enzymes that cleave specific bonds to activate or deactivate proteins. Naturally occurring proteases have various functions, including food digestion, cell growth, cell regulation, and protein adaptation [1]. One protease, botulinum neurotoxin (BoNT), has been successfully reprogrammed to cleave proteins it otherwise naturally wouldn’t be able to, bringing us a step closer to being able to directly edit the proteome. BoNT is secreted by the bacterium Clostridium botulinum [2]. Though one of the most toxic substances known to humans, it is used in a variety of items, including Botox injections and medication to treat muscle spasms. BoNT targets peripheral nerve terminals, cleaving proteins that aid in membrane fusion in eukaryotic cells and blocking the release of neurotransmitters from the end of the neuron. This disruption in neurotransmission results in paralysis [3]. Because it targets peripheral nerves, BoNT has the ability to easily enter neurons in large numbers, a capability not many therapeutics possess. Due to BoNT’s specificity and ease of transport into cells, collaborators from Harvard University and the Broad Institute of MIT chose to develop new versions of BoNT that would target any protein they programmed it to target. Using technology called PACE (Phage-Assisted Continuous Evolution) developed by David Liu of the Broad Institute, the researchers were able to rapidly evolve four novel BoNT proteases that cleaved completely different target proteins from their original targets [4]. These results are exciting for multiple reasons, but most importantly because proteases have never been programmed to cleave a completely different protein from their target protein [5]. The researchers are now looking to expand on their work and find human proteases that could be developed in a similar manner. While the BoNT proteases can enter cells easily, the immune system would eventually recognize these proteins as foreign and break them down. Modified human proteases, on the other hand, would have the ability to sneak past the immune system, allowing for a longer lifespan within cells. Proteomic editing enables the treatment of diseases that arise suddenly, such as the neurodegeneration that results from a stroke. Developing these tools to treat severe acute diseases will completely change the standard of care for these diseases in the future. We are now one step closer to adding proteomic editing to our molecular manipulation toolbox. References
[1] Ward O. Proteases. Comprehensive Biotechnology. 2019. [Cited 2021 Mar 20]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7151786/ [2] Nigam K, Nigam A. Botulinum Toxin. Indian Journal of Dermatology. 2010; 55, 1. [Cited 2021 Mar 20] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2856357/ [3] Lebeda F, Cer R, Mudunuri U, Stephens R, Singh B, Adler M. The Zinc-Dependent Protease Activity of the Botulinum Neurotoxins. Toxins. 2010; 2, 5. [Cited 2021 Mar 21] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3153231/ [4] Blum T, et al. Phage-assisted evolution of botulinum neurotoxin proteases with reprogrammed specificity. Science. 2021; 371, 6531. [Cited 2021 Mar 20] Available from: https://science.sciencemag.org/content/sci/371/6531/803.full.pdf?casa_token=tinnTaOWOcoAAAAA:YFmryF8XG2cW37m0wARmM2Mr8ieAIElibwCj_vTfpDfplZhBVQz4jnyltBC2ANMeEz4ZANw7kmi5dSk [5] ‘Miracle poison’ for novel therapeutics. Science Daily [Internet] [Cited 2021 Mar 20] Available from: https://www.sciencedaily.com/releases/2021/02/210225082527.htm
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