{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T12:16:35Z","timestamp":1788351395158,"version":"build-2803163510"},"reference-count":75,"publisher":"Wiley","issue":"28","license":[{"start":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T00:00:00Z","timestamp":1779148800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T00:00:00Z","timestamp":1779148800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01GM112940"],"award-info":[{"award-number":["R01GM112940"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Angew Chem Int Ed"],"published-print":{"date-parts":[[2026,7,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The heat shock protein 70 (Hsp70) family consists of ATP\u2010driven molecular chaperones essential for maintaining protein homeostasis (proteostasis) across all cell types, however, modulation of chaperone activity by small molecules remains challenging. In bacteria, a major Hsp70 called DnaK represents a putative antibacterial target, as it plays essential roles in growth, antibiotic resistance, and stress response. While Hsp70 inhibitors are in development as potential cancer and neurodegenerative disease treatments in humans, we lack generalizable methods to target Hsp70s across species. Here, we address how peptidomimetic scaffolds designed to inhibit proteases, exemplified by the drug telaprevir, interact with two different bacterial DnaKs to disrupt chaperone function. We perform extensive structure\u2010function studies of telaprevir analogs against DnaK to inform the design of synthetic unnatural peptide sequences with a range of inhibitory potencies. X\u2010ray crystallography analysis of telaprevir and several synthetic peptidomimetics reveal interactions with DnaK's substrate binding domain via ligand side chain recognition reminiscent of that observed in protease active sites, but in two orientations. These co\u2010complexes inspire the synthesis of shorter peptidomimetics capable of allosterically inhibiting DnaK's ATPase activity. Overall, this work demonstrates that chemical scaffolds devised for protease inhibition may be modified to disrupt Hsp70 chaperone activities.<\/jats:p>","DOI":"10.1002\/anie.1777033","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T16:38:42Z","timestamp":1779208722000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Reengineering Protease Inhibitors to Disrupt Hsp70 Chaperone Function"],"prefix":"10.1002","volume":"65","author":[{"given":"Aweon","family":"Richards","sequence":"first","affiliation":[{"name":"Department of Chemistry New York University  New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ascensi\u00f3n","family":"Ariza\u2010Mateos","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Pharmacology New York University Grossman School of Medicine  New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antara","family":"Ghosh","sequence":"additional","affiliation":[{"name":"Department of Chemistry New York University  New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Max","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Chemistry New York University  New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sterling","family":"Sandler","sequence":"additional","affiliation":[{"name":"Department of Chemistry New York University  New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Yardumian","sequence":"additional","affiliation":[{"name":"Department of Chemistry New York University  New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gideon","family":"Yawson","sequence":"additional","affiliation":[{"name":"Department of Chemistry New York University  New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy","family":"Baryza","sequence":"additional","affiliation":[{"name":"Vertex Pharmaceuticals  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Serganov","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Pharmacology New York University Grossman School of Medicine  New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0989-2565","authenticated-orcid":false,"given":"Tania J.","family":"Lupoli","sequence":"additional","affiliation":[{"name":"Department of Chemistry New York University  New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,19]]},"reference":[{"key":"e_1_2_9_2_1","first-page":"20","article-title":"Intra\u2010Molecular Pathways of Allosteric Control in Hsp70s","volume":"373","author":"Mayer M. P.","year":"1749","journal-title":"Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/76819"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/128_2012_323"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2011.12.007"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-060208-092442"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/1873-3468.13844"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aac4354"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-14245-4"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm100054f"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.250"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ab.2007.08.020"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1021\/ml400204n"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1021\/cb400356m"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.TM118.002813"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.8b00583"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2013.10.008"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm401552y"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm401551n"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.2174\/138161213804143699"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.202100459"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.0c02091"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA117.001575"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1004516"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00123-21"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpa.2023.102373"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.3389\/fchem.2022.798006"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23063150"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0124563"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.272.5268.1606"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2013.03.041"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/nsb0597-342"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/16.7.1501"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1994.1043"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M300922200"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.201000166"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2021.11.004"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-2836(84)90309-7"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2016962118"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.2c01631"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.3c00531"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xpro.2022.101381"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.2174\/09298665113206660111"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.0c00320"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.201000792"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1128\/JB.01131-08"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1021\/cb300063v"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1009567"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1000475"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0134(20000801)40:2<185::AID-PROT20>3.0.CO;2-X"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi061432a"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btz670"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.2000.4193"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(02)02752-7"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1038\/msb.2010.65"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.2174\/1875397300802010090"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.06.033"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.1128\/jb.169.1.283-290.1987"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1617644113"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2015.00057"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.202300261"},{"key":"e_1_2_9_62_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsinfecdis.1c00651"},{"key":"e_1_2_9_63_1","doi-asserted-by":"publisher","DOI":"10.1111\/mmi.14615"},{"key":"e_1_2_9_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2004.03.075"},{"key":"e_1_2_9_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2022.101697"},{"key":"e_1_2_9_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2024.107435"},{"key":"e_1_2_9_67_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2025.01.006"},{"key":"e_1_2_9_68_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-44933-9"},{"key":"e_1_2_9_69_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.26.15223"},{"key":"e_1_2_9_70_1","doi-asserted-by":"publisher","DOI":"10.2174\/092986709789352295"},{"key":"e_1_2_9_71_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi0012843"},{"key":"e_1_2_9_72_1","first-page":"873","volume-title":"Peptides: The Wave of the Future: Proceedings of the Second International and the Seventeenth American Peptide Symposium","author":"Otvos L.","year":"2001"},{"key":"e_1_2_9_73_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/47.5.575"},{"key":"e_1_2_9_74_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi002656a"},{"key":"e_1_2_9_75_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1747-0285.2006.00424.x"},{"key":"e_1_2_9_76_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2025.108800"}],"container-title":["Angewandte Chemie International Edition"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/anie.1777033","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/anie.1777033","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/anie.1777033","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T11:30:58Z","timestamp":1788348658000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/anie.1777033"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,19]]},"references-count":75,"journal-issue":{"issue":"28","published-print":{"date-parts":[[2026,7,6]]}},"alternative-id":["10.1002\/anie.1777033"],"URL":"https:\/\/doi.org\/10.1002\/anie.1777033","archive":["Portico"],"relation":{},"ISSN":["1433-7851","1521-3773"],"issn-type":[{"value":"1433-7851","type":"print"},{"value":"1521-3773","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,19]]},"assertion":[{"value":"2025-12-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-24","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-19","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e1777033"}}