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Treatment relies on just one drug, and new chemotherapies are needed. Schistosoma mansoni cathepsin B1 (SmCB1) is a critical peptidase for the digestion of host blood proteins and a validated drug target. We screened a library of peptidomimetic vinyl sulfones against SmCB1 and identified the most potent SmCB1 inhibitors reported to date that are active in the subnanomolar range with second order rate constants (k2nd) of \u223c2 \u00d7 105 M\u20131 s\u20131. High resolution crystal structures of the two best inhibitors in complex with SmCB1 were determined. Quantum chemical calculations of their respective binding modes identified critical hot spot interactions in the S1\u2032 and S2 subsites. The most potent inhibitor targets the S1\u2032 subsite with an N-hydroxysulfonic amide moiety and displays favorable functional properties, including bioactivity against the pathogen, selectivity for SmCB1 over human cathepsin B, and reasonable metabolic stability. Our results provide structural insights for the rational design of next-generation SmCB1 inhibitors as potential drugs to treat schistosomiasis.<\/jats:p>","DOI":"10.1021\/acsinfecdis.0c00501","type":"journal-article","created":{"date-parts":[[2020,11,11]],"date-time":"2020-11-11T15:43:17Z","timestamp":1605109397000},"page":"1077-1088","source":"Crossref","is-referenced-by-count":20,"title":["Druggable Hot Spots in the Schistosomiasis Cathepsin\nB1 Target Identified by Functional and Binding Mode Analysis of Potent\nVinyl Sulfone Inhibitors"],"prefix":"10.1021","volume":"7","author":[{"given":"Ade\u0301la","family":"Ji\u0301lkova\u0301","sequence":"first","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences , Flemingovo n. 2 , ,","place":["Prague, Czech Republic, 16610"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Rubes\u030cova\u0301","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences , Flemingovo n. 2 , ,","place":["Prague, Czech Republic, 16610"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jindr\u030cich","family":"Fanfrli\u0301k","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences , Flemingovo n. 2 , ,","place":["Prague, Czech Republic, 16610"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavla","family":"Fajtova\u0301","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences , Flemingovo n. 2 , ,","place":["Prague, Czech Republic, 16610"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavli\u0301na","family":"R\u030ceza\u0301c\u030cova\u0301","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences , Flemingovo n. 2 , ,","place":["Prague, Czech Republic, 16610"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jir\u030ci\u0301","family":"Brynda","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences , Flemingovo n. 2 , ,","place":["Prague, Czech Republic, 16610"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2607-8132","authenticated-orcid":true,"given":"Martin","family":"Leps\u030ci\u0301k","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences , Flemingovo n. 2 , ,","place":["Prague, Czech Republic, 16610"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena","family":"Mertli\u0301kova\u0301-Kaiserova\u0301","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences , Flemingovo n. 2 , ,","place":["Prague, Czech Republic, 16610"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cory D.","family":"Emal","sequence":"additional","affiliation":[{"name":"Eastern Michigan University , 541 Mark Jefferson , , ,","place":["Ypsilanti, Michigan, United States, 48197"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1240-2846","authenticated-orcid":true,"given":"Adam R.","family":"Renslo","sequence":"additional","affiliation":[{"name":"University of California San Francisco , 600 16th Street , , ,","place":["San Francisco, California, United States, 94143"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9785-5897","authenticated-orcid":true,"given":"William R.","family":"Roush","sequence":"additional","affiliation":[{"name":"The Scripps Research Institute , 130 Scripps Way , , ,","place":["Jupiter, Florida, United States, 33458"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9110-2018","authenticated-orcid":true,"given":"Martin","family":"Horn","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences , Flemingovo n. 2 , ,","place":["Prague, Czech Republic, 16610"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Conor R.","family":"Caffrey","sequence":"additional","affiliation":[{"name":"University of California San Diego , , 9500 Gilman Drive , , ,","place":["La Jolla, California, United States, 92093"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Mares\u030c","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences , Flemingovo n. 2 , ,","place":["Prague, Czech Republic, 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