{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T15:32:53Z","timestamp":1792423973006,"version":"4.5.0"},"update-to":[{"DOI":"10.1371\/journal.pntd.0010483","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,10,13]],"date-time":"2022-10-13T00:00:00Z","timestamp":1665619200000}}],"reference-count":95,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2022,10,3]],"date-time":"2022-10-03T00:00:00Z","timestamp":1664755200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["107475\/Z\/15\/Z FUGI"],"award-info":[{"award-number":["107475\/Z\/15\/Z FUGI"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002745","name":"Bayerische Forschungsstiftung","doi-asserted-by":"publisher","award":["AZ-1341-18"],"award-info":[{"award-number":["AZ-1341-18"]}],"id":[{"id":"10.13039\/501100002745","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003485","name":"Heiwa Nakajima Foundation","doi-asserted-by":"publisher","award":["AK-1-2019"],"award-info":[{"award-number":["AK-1-2019"]}],"id":[{"id":"10.13039\/501100003485","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      The potentially lethal zoonosis alveolar echinococcosis (AE) is caused by the metacestode larval stage of the tapeworm\n                      <jats:italic>Echinococcus multilocularis<\/jats:italic>\n                      . Current AE treatment options are limited and rely on surgery as well as on chemotherapy involving benzimidazoles (BZ). BZ treatment, however, is mostly parasitostatic only, must be given for prolonged time periods, and is associated with adverse side effects. Novel treatment options are thus urgently needed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methodology\/principal findings<\/jats:title>\n                    <jats:p>\n                      By applying a broad range of kinase inhibitors to\n                      <jats:italic>E<\/jats:italic>\n                      .\n                      <jats:italic>multilocularis<\/jats:italic>\n                      stem cell cultures we identified the proto-oncogene PIM kinase as a promising target for anti-AE chemotherapy. The gene encoding the respective\n                      <jats:italic>E<\/jats:italic>\n                      .\n                      <jats:italic>multilocularis<\/jats:italic>\n                      ortholog, EmPim, was characterized and\n                      <jats:italic>in situ<\/jats:italic>\n                      hybridization assays indicated its expression in parasite stem cells. By yeast two-hybrid assays we demonstrate interaction of EmPim with\n                      <jats:italic>E<\/jats:italic>\n                      .\n                      <jats:italic>multilocularis<\/jats:italic>\n                      CDC25, indicating an involvement of EmPim in parasite cell cycle regulation. Small molecule compounds SGI-1776 and CX-6258, originally found to effectively inhibit human PIM kinases, exhibited detrimental effects on\n                      <jats:italic>in vitro<\/jats:italic>\n                      cultured parasite metacestode vesicles and prevented the formation of mature vesicles from parasite stem cell cultures. To improve compound specificity for EmPim, we applied a high throughput\n                      <jats:italic>in silico<\/jats:italic>\n                      modelling approach, leading to the identification of compound Z196138710. When applied to\n                      <jats:italic>in vitro<\/jats:italic>\n                      cultured metacestode vesicles and parasite cell cultures, Z196138710 proved equally detrimental as SGI-1776 and CX-6258 but displayed significantly reduced toxicity towards human HEK293T and HepG2 cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Conclusions\/significance<\/jats:title>\n                    <jats:p>\n                      Repurposing of kinase inhibitors initially designed to affect mammalian kinases for helminth disease treatment is often hampered by adverse side effects of respective compounds on human cells. Here we demonstrate the utility of high throughput\n                      <jats:italic>in silico<\/jats:italic>\n                      approaches to design small molecule compounds of higher specificity for parasite cells. We propose EmPim as a promising target for respective approaches towards AE treatment.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pntd.0010483","type":"journal-article","created":{"date-parts":[[2022,10,3]],"date-time":"2022-10-03T13:51:33Z","timestamp":1664805093000},"page":"e0010483","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":21,"title":["Targeting Echinococcus multilocularis PIM kinase for improving anti-parasitic chemotherapy"],"prefix":"10.1371","volume":"16","author":[{"given":"Akito","family":"Koike","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Becker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Sennhenn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenny","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Hannus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6768-824X","authenticated-orcid":true,"given":"Klaus","family":"Brehm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,10,3]]},"reference":[{"key":"pntd.0010483.ref001","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/bs.apar.2016.11.002","article-title":"Ecology and life cycle patterns of Echinococcus species","volume":"95","author":"T Romig","year":"2017","journal-title":"Adv Parasitol"},{"key":"pntd.0010483.ref002","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/bs.apar.2016.09.001","article-title":"Echinococcus-host interactions at cellular and molecular levels","volume":"95","author":"K Brehm","year":"2017","journal-title":"Adv Parasitol"},{"issue":"5","key":"pntd.0010483.ref003","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1097\/QCO.0b013e32833d7516","article-title":"Clinical features and treatment of alveolar echinococcosis","volume":"23","author":"P. 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