{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T15:01:46Z","timestamp":1786719706049,"version":"build-2736575974"},"reference-count":44,"publisher":"American Chemical Society (ACS)","issue":"8","license":[{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Center for Emerging, Zoonotic, and Arthropod-borne Pathogens, Virginia Tech"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Protein synthesis represents an attractive target space for the development of antimalarials with novel modes of action. Natural-product inhibitors of the eukaryotic 80S ribosome can have potent antimalarial activity but are often poorly selective due to mammalian cytotoxicity. Blasticidin S is a microbially produced natural product that broadly inhibits prokaryotic and eukaryotic protein synthesis by binding to the ribosomal peptidyl transferase center. In this study, we explored the potential for improving the antimalarial potency and selectivity of the blasticidin S scaffold with semisynthetic analogs that are modified at the C6\u2019 and C4 sites. The two best analogs were 2 orders of magnitude more potent than blasticidin S against Plasmodium falciparum drug-sensitive and -resistant lines while displaying low cytotoxicity toward mammalian cells. These analogs exhibited improved kinetics of inhibition of protein synthesis in cultured parasites and arrested asexual development after the onset of plasmodial surface anion channel expression, a transporter required for nutrient acquisition and blasticidin S uptake. They also exhibited a dramatically improved speed of killing over blasticidin S. Molecular docking analysis revealed that these analogs are able to form more interactions with the P. falciparum ribosomal peptidyl transferase center than is blasticidin S, which is consistent with their increased potency. Together, these studies demonstrate the feasibility of generating blasticidin S analogs with potent antimalarial activity and provide a roadmap for further development.<\/jats:p>","DOI":"10.1021\/acsinfecdis.6c00362","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T14:32:38Z","timestamp":1785853958000},"page":"2788-2798","source":"Crossref","is-referenced-by-count":0,"title":["Development\nof Semisynthetic Blasticidin S Analogs\nwith Potent and Fast-Killing Antimalarial Activity"],"prefix":"10.1021","volume":"12","author":[{"given":"Katherine R.","family":"Fike","sequence":"first","affiliation":[{"name":"Virginia Tech , , , ,","place":["Blacksburg, Virginia, United States, 24061"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cole","family":"Gannett","sequence":"additional","affiliation":[{"name":"Virginia Tech , , , ,","place":["Blacksburg, Virginia, United States, 24061"]},{"name":"Virginia Tech , , , ,","place":["Blacksburg, Virginia, United States, 24061"]},{"name":"Virginia Tech , , , ,","place":["Blacksburg, Virginia, United States, 24061"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastazja M.","family":"Kiselka","sequence":"additional","affiliation":[{"name":"Virginia Tech , , , ,","place":["Blacksburg, Virginia, United States, 24061"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kateland","family":"Tiller","sequence":"additional","affiliation":[{"name":"Virginia Tech , , , ,","place":["Blacksburg, Virginia, United States, 24061"]},{"name":"Virginia Tech , , , ,","place":["Blacksburg, Virginia, United States, 24061"]},{"name":"Virginia Tech , , , ,","place":["Blacksburg, Virginia, United States, 24061"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toheeb","family":"Ajasa","sequence":"additional","affiliation":[{"name":"Virginia Tech , , , ,","place":["Blacksburg, Virginia, United States, 24061"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Weger-Lucarelli","sequence":"additional","affiliation":[{"name":"Virginia Tech , , , ,","place":["Blacksburg, Virginia, United States, 24061"]},{"name":"Virginia Tech , , , ,","place":["Blacksburg, Virginia, United States, 24061"]},{"name":"Virginia Tech , , , ,","place":["Blacksburg, Virginia, United States, 24061"]},{"name":"Virginia Tech , , , ,","place":["Blacksburg, Virginia, United States, 24061"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6951-8228","authenticated-orcid":true,"given":"Anne M.","family":"Brown","sequence":"additional","affiliation":[{"name":"Virginia Tech , , , ,","place":["Blacksburg, Virginia, United States, 24061"]},{"name":"Virginia Tech , , , ,","place":["Blacksburg, Virginia, United States, 24061"]},{"name":"Virginia Tech , , , ,","place":["Blacksburg, Virginia, United States, 24061"]},{"name":"University Libraries, Virginia Tech , , , ,","place":["Blacksburg, Virginia, United States, 24061"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5357-5279","authenticated-orcid":true,"given":"Andrew N.","family":"Lowell","sequence":"additional","affiliation":[{"name":"Virginia Tech , , , ,","place":["Blacksburg, Virginia, United States, 24061"]},{"name":"Virginia Tech , , , ,","place":["Blacksburg, Virginia, United States, 24061"]},{"name":"Virginia Tech , , , ,","place":["Blacksburg, Virginia, United States, 24061"]},{"name":"Virginia Tech , , , ,","place":["Blacksburg, Virginia, United States, 24061"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8827-6877","authenticated-orcid":true,"given":"Michael","family":"Klemba","sequence":"additional","affiliation":[{"name":"Virginia Tech , , , ,","place":["Blacksburg, Virginia, United States, 24061"]},{"name":"Virginia Tech , , , ,","place":["Blacksburg, Virginia, United States, 24061"]},{"name":"Virginia Tech , , , ,","place":["Blacksburg, Virginia, United States, 24061"]},{"name":"Virginia Tech , , , ,","place":["Blacksburg, Virginia, United States, 24061"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,1]]},"reference":[{"key":"2026081410073687200_cit1","unstructured":"World Malaria Report 2025: Addressing the Threat of Antimalarial\nDrug Resistance; World Health Organization: 2025."},{"issue":"10","key":"2026081410073687200_cit2","doi-asserted-by":"publisher","first-page":"3485","DOI":"10.1128\/AAC.00527-07","article-title":"Multiple\nantibiotics exert delayed effects against\nthe Plasmodium falciparum apicoplast","volume":"51","author":"Dahl","year":"2007","journal-title":"Antimicrob. Agents Chemother."},{"issue":"2","key":"2026081410073687200_cit3","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1016\/j.molbiopara.2007.01.005","article-title":"The effects\nof anti-bacterials on the malaria parasite Plasmodium falciparum","volume":"152","author":"Goodman","year":"2007","journal-title":"Mol.\nBiochem. Parasitol."},{"issue":"7556","key":"2026081410073687200_cit4","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1038\/nature14451","article-title":"A novel\nmultiple-stage antimalarial agent that inhibits protein synthesis","volume":"522","author":"Baragan\u0303a","year":"2015","journal-title":"Nature"},{"issue":"1","key":"2026081410073687200_cit5","doi-asserted-by":"publisher","DOI":"10.1186\/s12936-018-2616-7","article-title":"The Plasmodium falciparum cytoplasmic translation apparatus:\na promising therapeutic target not yet exploited by clinically approved\nanti-malarials","volume":"17","author":"Sheridan","year":"2018","journal-title":"Malar. J."},{"key":"2026081410073687200_cit6","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1146\/annurev-micro-032421-121210","article-title":"Targeting aminoacyl tRNA synthetases\nfor antimalarial\ndrug development","volume":"77","author":"Xie","year":"2023","journal-title":"Annu. Rev. Microbiol."},{"issue":"1","key":"2026081410073687200_cit7","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/0022-510X(78)90183-1","article-title":"Experimental (\u2212)\nemetine myopathy. Ultrastructural\nand morphometric observations","volume":"39","author":"Bindoff","year":"1978","journal-title":"J. Neurol. 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Acta, Biomembr."},{"issue":"2","key":"2026081410073687200_cit36","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0030949","article-title":"P. falciparum in vitro killing rates allow to discriminate\nbetween different antimalarial mode-of-action","volume":"7","author":"Sanz","year":"2012","journal-title":"PLoS One"},{"issue":"17","key":"2026081410073687200_cit37","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2021.167035","article-title":"Cation-pi Interactions and their\nfunctional roles in\nmembrane proteins","volume":"433","author":"Infield","year":"2021","journal-title":"J. Mol. Biol."},{"issue":"4","key":"2026081410073687200_cit38","doi-asserted-by":"publisher","DOI":"10.1128\/MMBR.00104-21","article-title":"The peptidyl transferase\ncenter: a window to the past","volume":"85","author":"Tirumalai","year":"2021","journal-title":"Microbiol. Mol.\nBiol. 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U.S.A."},{"issue":"4","key":"2026081410073687200_cit41","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpara.2025.09.009","article-title":"Defining the\nminimal enzymatic requirements for fatty acid scavenging from lysophosphatidylcholine\nby erythrocytic Plasmodium falciparum","volume":"56","author":"Liu","year":"2026","journal-title":"Int. J. Parasitol."},{"issue":"7","key":"2026081410073687200_cit42","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0235798","article-title":"Use of a highly specific kinase inhibitor\nfor rapid, simple and precise synchronization of Plasmodium falciparum and Plasmodium knowlesi asexual blood-stage parasites","volume":"15","author":"Ressurreic\u0327a\u0303o","year":"2020","journal-title":"PLoS One"},{"issue":"22","key":"2026081410073687200_cit43","doi-asserted-by":"publisher","first-page":"7145","DOI":"10.1021\/jacs.5b02383","article-title":"CalFluors: A universal motif for\nfluorogenic azide probes across the visible spectrum","volume":"137","author":"Shieh","year":"2015","journal-title":"J. Am. Chem. Soc."},{"issue":"11","key":"2026081410073687200_cit44","doi-asserted-by":"publisher","DOI":"10.1002\/pro.4792","article-title":"UCSF ChimeraX:\nTools for structure\nbuilding and analysis","volume":"32","author":"Meng","year":"2023","journal-title":"Protein Sci."}],"container-title":["ACS Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsinfecdis.6c00362","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article-pdf\/12\/8\/2788\/66353351\/acsinfecdis.6c00362.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article-pdf\/12\/8\/2788\/66353351\/acsinfecdis.6c00362.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T14:16:47Z","timestamp":1786717007000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article\/12\/8\/2788\/5238242\/Development-of-Semisynthetic-Blasticidin-S-Analogs"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,1]]},"references-count":44,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8,1]]},"published-print":{"date-parts":[[2026,8,14]]}},"URL":"https:\/\/doi.org\/10.1021\/acsinfecdis.6c00362","relation":{},"ISSN":["2373-8227"],"issn-type":[{"value":"2373-8227","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,1]]}}}