{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T00:49:32Z","timestamp":1760316572390,"version":"build-2065373602"},"reference-count":72,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2022,11,24]],"date-time":"2022-11-24T00:00:00Z","timestamp":1669248000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["140931","72667"],"award-info":[{"award-number":["140931","72667"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Chemistry A European J"],"published-print":{"date-parts":[[2023,1,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Phosphatidylinositol phosphate kinases (PIPKs) produce lipid signaling molecules and have been attracting increasing attention as drug targets for cancer, neurodegenerative diseases, and viral infection. Given the potential cross\u2010inhibition of kinases and other ATP\u2010utilizing enzymes by ATP\u2010competitive inhibitors, targeting the unique lipid substrate binding site represents a superior strategy for PIPK inhibition. Here, by taking advantage of the nearly identical stereochemistry between <jats:italic>myo<\/jats:italic>\u2010inositol and D\u2010galactose, we designed and synthesized a panel of D\u2010galactosyl lysophospholipids, one of which was found to be a selective substrate of phosphatidylinositol 4\u2010phosphate 5\u2010kinase. Derivatization of this compound led to the discovery of a human PIKfyve inhibitor with an apparent IC<jats:sub>50<\/jats:sub> of 6.2\u2005\u03bcM, which significantly potentiated the inhibitory effect of Apilimod, an ATP\u2010competitive PIKfyve inhibitor under clinical trials against SARS\u2010CoV\u20102 infection and amyotrophic lateral sclerosis. Our results provide the proof of concept that D\u2010galactose\u2010based phosphoinositide mimetics can be developed into artificial substrates and new inhibitors of PIPKs.<\/jats:p>","DOI":"10.1002\/chem.202202083","type":"journal-article","created":{"date-parts":[[2022,11,24]],"date-time":"2022-11-24T22:06:57Z","timestamp":1669327617000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Rational Design and Synthesis of D\u2010galactosyl Lysophospholipids as Selective Substrates and non\u2010ATP\u2010competitive Inhibitors of Phosphatidylinositol Phosphate Kinases"],"prefix":"10.1002","volume":"29","author":[{"given":"Mengxia","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Chemistry Michigan State University  Michigan MI 48824 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Michigan State University  Michigan MI 48824 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dexin","family":"Sui","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Michigan State University  Michigan MI 48824 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Canchai","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Microbiology &amp; Molecular Genetics Michigan State University  Michigan MI 48824 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dohun","family":"Pyeon","sequence":"additional","affiliation":[{"name":"Department of Microbiology &amp; Molecular Genetics Michigan State University  Michigan MI 48824 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6468-5526","authenticated-orcid":false,"given":"Xuefei","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Chemistry Michigan State University  Michigan MI 48824 USA"},{"name":"Department of Biomedical Engineering Michigan State University  Michigan MI 48824 USA"},{"name":"Institute for Quantitative Health Science and Engineering Michigan State University  Michigan MI 48824 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6657-9826","authenticated-orcid":false,"given":"Jian","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Chemistry Michigan State University  Michigan MI 48824 USA"},{"name":"Department of Biochemistry and Molecular Biology Michigan State University  Michigan MI 48824 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,11,24]]},"reference":[{"key":"e_1_2_11_1_1","unstructured":"\u00a0"},{"key":"e_1_2_11_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature05185"},{"key":"e_1_2_11_3_2","doi-asserted-by":"publisher","DOI":"10.1042\/BCJ20180022"},{"key":"e_1_2_11_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2019.12.007"},{"key":"e_1_2_11_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms9205"},{"key":"e_1_2_11_6_2","doi-asserted-by":"publisher","DOI":"10.1042\/BCJ20180326"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.4161\/cam.21192"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.15.8741"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.32.20292"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2018.03.037"},{"key":"e_1_2_11_11_1","unstructured":"\u00a0"},{"key":"e_1_2_11_12_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201412127"},{"key":"e_1_2_11_13_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.222364"},{"key":"e_1_2_11_14_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0854.2008.00754.x"},{"key":"e_1_2_11_15_2","doi-asserted-by":"publisher","DOI":"10.1247\/csf.17003"},{"key":"e_1_2_11_16_1","unstructured":"\u00a0"},{"key":"e_1_2_11_17_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1405801111"},{"key":"e_1_2_11_18_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-20-3371"},{"key":"e_1_2_11_19_2","volume":"118","author":"Chen S.","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"e_1_2_11_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.09.057"},{"journal-title":"FEBS Lett.","year":"2021","author":"Arora G. K.","key":"e_1_2_11_21_2"},{"key":"e_1_2_11_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-02287-5"},{"key":"e_1_2_11_23_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-09-736892"},{"key":"e_1_2_11_24_1","unstructured":"\u00a0"},{"key":"e_1_2_11_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4490"},{"key":"e_1_2_11_26_2","first-page":"685800","author":"Staats K. A.","year":"2019","journal-title":"bioRxiv."},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2014.04.006"},{"key":"e_1_2_11_28_1","unstructured":"\u00a0"},{"key":"e_1_2_11_29_2","doi-asserted-by":"publisher","DOI":"10.3390\/v12101124"},{"key":"e_1_2_11_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2577-1"},{"key":"e_1_2_11_31_1","unstructured":"\u00a0"},{"key":"e_1_2_11_32_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2007837117"},{"key":"e_1_2_11_33_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00975-21"},{"key":"e_1_2_11_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2020.104990"},{"key":"e_1_2_11_35_1","unstructured":"\u00a0"},{"key":"e_1_2_11_36_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.0c00227"},{"key":"e_1_2_11_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2013.05.010"},{"key":"e_1_2_11_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2020.02.003"},{"key":"e_1_2_11_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2021.116557"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2011.08.004"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M001010200"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2005.04.011"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1021\/cb5008376"},{"key":"e_1_2_11_44_1","unstructured":"\u00a0"},{"key":"e_1_2_11_45_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature12782"},{"key":"e_1_2_11_46_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.531426"},{"key":"e_1_2_11_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature22337"},{"key":"e_1_2_11_48_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-019-0954-x"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tet.2008.08.023"},{"key":"e_1_2_11_50_1","unstructured":"\u00a0"},{"key":"e_1_2_11_51_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.370155"},{"key":"e_1_2_11_52_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.1600925"},{"key":"e_1_2_11_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2019.05.004"},{"key":"e_1_2_11_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.plipres.2012.09.002"},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1522112113"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.1038\/aps.2015.71"},{"key":"e_1_2_11_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2019.114771"},{"key":"e_1_2_11_58_1","unstructured":"\u00a0"},{"key":"e_1_2_11_59_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R117.000629"},{"key":"e_1_2_11_60_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.202259"},{"key":"e_1_2_11_61_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.144.3.497"},{"key":"e_1_2_11_62_1","unstructured":"\u00a0"},{"key":"e_1_2_11_63_2","doi-asserted-by":"publisher","DOI":"10.1111\/febs.15194"},{"key":"e_1_2_11_64_2","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20141333"},{"key":"e_1_2_11_65_1","unstructured":"\u00a0"},{"key":"e_1_2_11_66_2","doi-asserted-by":"publisher","DOI":"10.1021\/jo0206418"},{"key":"e_1_2_11_67_2","doi-asserted-by":"publisher","DOI":"10.1039\/B913399B"},{"key":"e_1_2_11_68_1","doi-asserted-by":"publisher","DOI":"10.1039\/b616450a"},{"key":"e_1_2_11_69_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.15.9907"},{"key":"e_1_2_11_70_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40121-020-00382-7"},{"key":"e_1_2_11_71_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2012.09.006"},{"key":"e_1_2_11_72_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0161-6420(96)30675-1"}],"container-title":["Chemistry \u2013 A European Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/chem.202202083","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/chem.202202083","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/chem.202202083","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T16:53:26Z","timestamp":1760288006000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/chem.202202083"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,24]]},"references-count":72,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2023,1,9]]}},"alternative-id":["10.1002\/chem.202202083"],"URL":"https:\/\/doi.org\/10.1002\/chem.202202083","archive":["Portico"],"relation":{},"ISSN":["0947-6539","1521-3765"],"issn-type":[{"type":"print","value":"0947-6539"},{"type":"electronic","value":"1521-3765"}],"subject":[],"published":{"date-parts":[[2022,11,24]]},"assertion":[{"value":"2022-07-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-11-24","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e202202083"}}