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Some serotypes, notably serotype A and B, can cause persistent paralysis lasting for several months. Because of their potency and persistence, botulinum neurotoxins are now used to manage several clinical conditions, and there is interest in expanding their clinical applications using engineered toxins with novel substrate specificities. It will also be beneficial to engineer toxins with tunable persistence. We have investigated the potential use of small-molecule proteolysis-targeting chimeras (PROTACs) to vary the persistence of modified recombinant botulinum neurotoxins. We also describe a complementary approach that has potential relevance for botulism treatment. This second approach uses a camelid heavy chain antibody directed against botulinum neurotoxin that is modified to bind the PROTAC. These strategies provide proof of principle for the use of two different approaches to fine tune the persistence of botulinum neurotoxins by selectively targeting their catalytic light chains for proteasomal degradation.<\/jats:p>","DOI":"10.3390\/ijms25137472","type":"journal-article","created":{"date-parts":[[2024,7,8]],"date-time":"2024-07-08T12:21:03Z","timestamp":1720441263000},"page":"7472","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The Degradation of Botulinum Neurotoxin Light Chains Using PROTACs"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9624-1092","authenticated-orcid":false,"given":"Yien Che","family":"Tsai","sequence":"first","affiliation":[{"name":"Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Loren","family":"Kozar","sequence":"additional","affiliation":[{"name":"Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zo P.","family":"Mawi","sequence":"additional","affiliation":[{"name":"Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2198-1325","authenticated-orcid":false,"given":"Konstantin","family":"Ichtchenko","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9738-1361","authenticated-orcid":false,"given":"Charles B.","family":"Shoemaker","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Global Health, Tufts University Cummings School of Veterinary Medicine, Grafton, MA 01536, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5703-4565","authenticated-orcid":false,"given":"Patrick M.","family":"McNutt","sequence":"additional","affiliation":[{"name":"Wake Forest Research Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7865-7702","authenticated-orcid":false,"given":"Allan M.","family":"Weissman","sequence":"additional","affiliation":[{"name":"Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA"},{"name":"Women\u2019s Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,8]]},"reference":[{"key":"ref_1","first-page":"93","article-title":"Clostridial neurotoxins: Handling and action at the cellular and molecular level","volume":"129","author":"Habermann","year":"1986","journal-title":"Curr. 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