{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,5]],"date-time":"2025-10-05T11:51:23Z","timestamp":1759665083165,"version":"3.41.2"},"reference-count":75,"publisher":"American Society for Microbiology","issue":"24","license":[{"start":{"date-parts":[[2018,12,15]],"date-time":"2018-12-15T00:00:00Z","timestamp":1544832000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","award":["W81XWH-14-C-0070"],"award-info":[{"award-number":["W81XWH-14-C-0070"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Appl Environ Microbiol"],"published-print":{"date-parts":[[2018,12,15]]},"abstract":"<jats:p>\n            The long-lasting endopeptidase activity of BoNT is a critical biological activity inside the nerve cell, as it prompts proteolysis of the SNARE proteins, involved in the exocytosis of the neurotransmitter acetylcholine. Thus, the BoNT endopeptidase activity is an appropriate clinical target for designing new small-molecule antidotes against BoNT with the potential to reverse the paralysis syndrome of botulism. In principle, small-molecule inhibitors (SMIs) can gain entry into BoNT-intoxicated cells if they have a suitable octanol-water partition coefficient (log\n            <jats:italic>P<\/jats:italic>\n            ) value and other favorable characteristics (P. Leeson, Nature 481:455\u2013456, 2012,\n            <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/doi.org\/10.1038\/481455a\">https:\/\/doi.org\/10.1038\/481455a<\/jats:ext-link>\n            ). Several efforts have been made in the past to develop SMIs, but inhibitors effective under\n            <jats:italic>in vitro<\/jats:italic>\n            conditions have not in general been effective\n            <jats:italic>in vivo<\/jats:italic>\n            or in cellular models (L. M. Eubanks, M. S. Hixon, W. Jin, S. Hong, et al., Proc Natl Acad Sci U S A 104:2602\u20132607, 2007,\n            <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/doi.org\/10.1073\/pnas.0611213104\">https:\/\/doi.org\/10.1073\/pnas.0611213104<\/jats:ext-link>\n            ). The difference between the\n            <jats:italic>in vitro<\/jats:italic>\n            and cellular efficacy presumably results from difficulties experienced by the compounds in crossing the cell membrane, in conjunction with poor bioavailability and high cytotoxicity. The screened nitrophenyl psoralen (NPP) effectively antagonized BoNT\/A in both\n            <jats:italic>in vitro<\/jats:italic>\n            and\n            <jats:italic>ex vivo<\/jats:italic>\n            assays. Importantly, NPP inhibited the BoNT\/A light chain but not other general zinc endopeptidases, such as thermolysin, suggesting high selectivity for its target. Small-molecule (nonpeptidic) inhibitors have better oral bioavailability, better stability, and better tissue and cell permeation than antitoxins or peptide inhibitors.\n          <\/jats:p>","DOI":"10.1128\/aem.01280-18","type":"journal-article","created":{"date-parts":[[2018,10,16]],"date-time":"2018-10-16T10:53:31Z","timestamp":1539687211000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":11,"title":["Natural Compounds and Their Analogues as Potent Antidotes against the Most Poisonous Bacterial Toxin"],"prefix":"10.1128","volume":"84","author":[{"given":"Kruti B.","family":"Patel","sequence":"first","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Massachusetts Dartmouth, North Dartmouth, Massachusetts, USA"},{"name":"Institute of Advanced Sciences, Dartmouth, Massachusetts, 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