{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T15:34:05Z","timestamp":1781278445398,"version":"3.54.1"},"reference-count":87,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,1,18]],"date-time":"2022-01-18T00:00:00Z","timestamp":1642464000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,1,18]],"date-time":"2022-01-18T00:00:00Z","timestamp":1642464000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001501","name":"University Grants Commission","doi-asserted-by":"publisher","award":["F.3.3.\/2016 DRS II UGC-SAP II"],"award-info":[{"award-number":["F.3.3.\/2016 DRS II UGC-SAP II"]}],"id":[{"id":"10.13039\/501100001501","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001409","name":"Department of Science and Technology, Ministry of Science and Technology, India","doi-asserted-by":"publisher","award":["RC\/2014\/7114"],"award-info":[{"award-number":["RC\/2014\/7114"]}],"id":[{"id":"10.13039\/501100001409","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001412","name":"Council of Scientific and Industrial Research, India","doi-asserted-by":"publisher","award":["37(1682)\/17\/EMR-II"],"award-info":[{"award-number":["37(1682)\/17\/EMR-II"]}],"id":[{"id":"10.13039\/501100001412","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001407","name":"Department of Biotechnology, Ministry of Science and Technology, India","doi-asserted-by":"publisher","award":["BT\/PR15422\/MED\/30\/1705\/2016"],"award-info":[{"award-number":["BT\/PR15422\/MED\/30\/1705\/2016"]}],"id":[{"id":"10.13039\/501100001407","id-type":"DOI","asserted-by":"publisher"}]},{"name":"University of Delhi, India","award":["lOE\/FRP\/LS\/2020\/27"],"award-info":[{"award-number":["lOE\/FRP\/LS\/2020\/27"]}]},{"DOI":"10.13039\/501100007063","name":"University of Delhi","doi-asserted-by":"publisher","award":["IoE\/2021\/12\/FRP"],"award-info":[{"award-number":["IoE\/2021\/12\/FRP"]}],"id":[{"id":"10.13039\/501100007063","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Malaria has endured as a global epidemic since ages and its eradication poses an immense challenge due to the complex life cycle of the causative pathogen and its tolerance to a myriad of therapeutics. PfUCHL3, a member of the ubiquitin C-terminal hydrolase (UCH) family of deubiquitinases (DUBs) is cardinal for parasite survival and emerges as a promising therapeutic target. In this quest, we employed a combination of computational and experimental approaches to identify PfUCHL3 inhibitors as novel anti-malarials. The Pathogen Box library was screened against the crystal structure of PfUCHL3 (PDB ID: 2WE6) and its human ortholog (PDB ID: 1XD3). Fifty molecules with better comparative score, bioavailability and druglikeliness were subjected to in-vitro enzyme inhibition assay and among them only two compounds effectively inhibited PfUCHL3 activity at micro molar concentrations. Both MMV676603 and MMV688704 exhibited anti-plasmodial activity by altering the parasite phenotype at late stages of the asexual life cycle and inducing the accumulation of polyubiquitinated substrates. In addition, both the compounds were non-toxic and portrayed high selectivity window for the parasite over mammalian cells. This is the first comprehensive study to demonstrate the anti-malarial efficacy of PfUCHL3 inhibitors and opens new avenues to exploit UCH family of DUBs as a promising target for the development of next generation anti-malaria therapy.<\/jats:p>","DOI":"10.1038\/s41598-021-04619-4","type":"journal-article","created":{"date-parts":[[2022,1,18]],"date-time":"2022-01-18T11:03:20Z","timestamp":1642503800000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Repurposing the Pathogen Box compounds for identification of potent anti-malarials against blood stages of Plasmodium falciparum with PfUCHL3 inhibitory activity"],"prefix":"10.1038","volume":"12","author":[{"given":"Hina","family":"Bharti","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aakriti","family":"Singal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manisha","family":"Saini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pradeep Singh","family":"Cheema","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohsin","family":"Raza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suman","family":"Kundu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alo","family":"Nag","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,1,18]]},"reference":[{"key":"4619_CR1","doi-asserted-by":"publisher","first-page":"299","DOI":"10.30875\/60123dd4-en","volume-title":"World Malaria Report 2020","author":"World Health Organization","year":"2020","unstructured":"World Health Organization. World malaria report 2020. World Health Organization (WHO), 299 (2020)."},{"key":"4619_CR2","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1038\/nature03342","volume":"434","author":"RW Snow","year":"2005","unstructured":"Snow, R. W., Guerra, C. A., Noor, A. M., Myint, H. Y. & Hay, S. I. The global distribution of clinical episodes of Plasmodium falciparum malaria. Nature 434, 214\u2013217 (2005).","journal-title":"Nature"},{"key":"4619_CR3","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1038\/nature15535","volume":"526","author":"S Bhatt","year":"2015","unstructured":"Bhatt, S. et al. The effect of malaria control on Plasmodium falciparum in Africa between 2000 and 2015. Nature 526, 207\u2013211 (2015).","journal-title":"Nature"},{"key":"4619_CR4","doi-asserted-by":"publisher","first-page":"849","DOI":"10.1038\/nrmicro3138","volume":"11","author":"EL Flannery","year":"2013","unstructured":"Flannery, E. L., Chatterjee, A. K. & Winzeler, E. A. Antimalarial drug discovery\u2014Approaches and progress towards new medicines. Nat. Rev. Microbiol. 11, 849\u2013862 (2013).","journal-title":"Nat. Rev. Microbiol."},{"key":"4619_CR5","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1016\/j.pt.2015.11.015","volume":"32","author":"B Galatas","year":"2016","unstructured":"Galatas, B., Bassat, Q. & Mayor, A. Malaria parasites in the asymptomatic: Looking for the hay in the haystack. Trends Parasitol. 32, 296\u2013308 (2016).","journal-title":"Trends Parasitol."},{"key":"4619_CR6","doi-asserted-by":"publisher","first-page":"1960","DOI":"10.1016\/S0140-6736(12)60484-X","volume":"379","author":"AP Phyo","year":"2012","unstructured":"Phyo, A. P. et al. Emergence of artemisinin-resistant malaria on the western border of Thailand: A longitudinal study. Lancet 379, 1960\u20131966 (2012).","journal-title":"Lancet"},{"key":"4619_CR7","doi-asserted-by":"publisher","first-page":"17412","DOI":"10.1038\/srep17412","volume":"5","author":"M Imwong","year":"2015","unstructured":"Imwong, M. et al. An outbreak of artemisinin resistant falciparum malaria in Eastern Thailand. Sci. Rep. 5, 17412 (2015).","journal-title":"Sci. Rep."},{"key":"4619_CR8","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1056\/NEJMoa1314981","volume":"371","author":"EA Ashley","year":"2014","unstructured":"Ashley, E. A. et al. Spread of artemisinin resistance in Plasmodium falciparum malaria. N. Engl. J. Med. 371, 411\u2013423 (2014).","journal-title":"N. Engl. J. Med."},{"key":"4619_CR9","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1097\/QCO.0000000000000199","volume":"28","author":"RM Fairhurst","year":"2015","unstructured":"Fairhurst, R. M. Understanding artemisinin-resistant malaria: what a difference a year makes. Curr. Opin. Infect. Dis. 28, 417\u2013425 (2015).","journal-title":"Curr. Opin. Infect. Dis."},{"key":"4619_CR10","doi-asserted-by":"publisher","first-page":"917","DOI":"10.1038\/nm.4381","volume":"23","author":"B Blasco","year":"2017","unstructured":"Blasco, B., Leroy, D. & Fidock, D. A. Antimalarial drug resistance: Linking Plasmodium falciparum parasite biology to the clinic. Nat. Med. 23, 917\u2013928 (2017).","journal-title":"Nat. Med."},{"key":"4619_CR11","doi-asserted-by":"publisher","first-page":"e15","DOI":"10.1016\/S1473-3099(16)30269-9","volume":"17","author":"NJ White","year":"2017","unstructured":"White, N. J. Does antimalarial mass drug administration increase or decrease the risk of resistance?. Lancet Infect. Dis. 17, e15\u2013e20 (2017).","journal-title":"Lancet Infect. Dis."},{"key":"4619_CR12","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/S0140-6736(15)60721-8","volume":"386","author":"RTS,S Clinical Trials Partnership","year":"2015","unstructured":"RTS,S Clinical Trials Partnership. Efficacy and safety of RTS, S\/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: Final results of a phase 3, individually randomised, controlled trial. Lancet 386, 31\u201345 (2015).","journal-title":"Lancet"},{"key":"4619_CR13","doi-asserted-by":"publisher","first-page":"2029","DOI":"10.2174\/1568026619666181129125950","volume":"18","author":"H Bharti","year":"2018","unstructured":"Bharti, H., Singal, A., Raza, M., Ghosh, P. & Nag, A. Ionophores as potent anti-malarials: A miracle in the making. Curr. Top. Med. Chem. 18, 2029\u20132041 (2018).","journal-title":"Curr. Top. Med. Chem."},{"key":"4619_CR14","doi-asserted-by":"publisher","first-page":"e1000214","DOI":"10.1371\/journal.ppat.1000214","volume":"4","author":"K Ganesan","year":"2008","unstructured":"Ganesan, K. et al. A genetically hard-wired metabolic transcriptome in Plasmodium falciparum fails to mount protective responses to lethal antifolates. PLoS Pathog. 4, e1000214 (2008).","journal-title":"PLoS Pathog."},{"key":"4619_CR15","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/j.molbiopara.2009.08.001","volume":"168","author":"D-WD Chung","year":"2009","unstructured":"Chung, D.-W.D., Ponts, N., Cervantes, S. & Le Roch, K. G. Post-translational modifications in Plasmodium: More than you think!. Mol. Biochem. Parasitol. 168, 123\u2013134 (2009).","journal-title":"Mol. Biochem. Parasitol."},{"key":"4619_CR16","doi-asserted-by":"publisher","first-page":"40320","DOI":"10.1074\/jbc.M111.238790","volume":"286","author":"N Ponts","year":"2011","unstructured":"Ponts, N. et al. Unraveling the ubiquitome of the human malaria parasite. J. Biol. Chem. 286, 40320\u201340330 (2011).","journal-title":"J. Biol. Chem."},{"key":"4619_CR17","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41467-017-00267-3","volume":"8","author":"SC Nair","year":"2017","unstructured":"Nair, S. C. et al. A Plasmodium yoelii HECT-like E3 ubiquitin ligase regulates parasite growth and virulence. Nat. Commun. 8, 1\u201314 (2017).","journal-title":"Nat. Commun."},{"key":"4619_CR18","doi-asserted-by":"publisher","first-page":"e1008640","DOI":"10.1371\/journal.ppat.1008640","volume":"16","author":"JL Green","year":"2020","unstructured":"Green, J. L. et al. Ubiquitin activation is essential for schizont maturation in Plasmodium falciparum blood-stage development. PLoS Pathog. 16, e1008640 (2020).","journal-title":"PLoS Pathog."},{"key":"4619_CR19","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ijpddr.2011.12.001","volume":"2","author":"MN Aminake","year":"2012","unstructured":"Aminake, M. N., Arndt, H.-D. & Pradel, G. The proteasome of malaria parasites: A multi-stage drug target for chemotherapeutic intervention?. Int. J. Parasitol. Drugs Drug Resist. 2, 1\u201310 (2012).","journal-title":"Int. J. Parasitol. Drugs Drug Resist."},{"key":"4619_CR20","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s40360-017-0147-4","volume":"18","author":"J Jain","year":"2017","unstructured":"Jain, J., Jain, S. K., Walker, L. A. & Tekwani, B. L. Inhibitors of ubiquitin E3 ligase as potential new antimalarial drug leads. BMC Pharmacol. Toxicol. 18, 1\u201310 (2017).","journal-title":"BMC Pharmacol. Toxicol."},{"key":"4619_CR21","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1016\/j.pt.2017.05.009","volume":"33","author":"CL Ng","year":"2017","unstructured":"Ng, C. L., Fidock, D. A. & Bogyo, M. Protein degradation systems as antimalarial therapeutic targets. Trends Parasitol. 33, 731\u2013743 (2017).","journal-title":"Trends Parasitol."},{"key":"4619_CR22","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1146\/annurev-biochem-060310-170328","volume":"81","author":"D Komander","year":"2012","unstructured":"Komander, D. & Rape, M. The ubiquitin code. Annu. Rev. Biochem. 81, 203\u2013229 (2012).","journal-title":"Annu. Rev. Biochem."},{"key":"4619_CR23","doi-asserted-by":"publisher","first-page":"7751","DOI":"10.1073\/pnas.86.20.7751","volume":"86","author":"E Eytan","year":"1989","unstructured":"Eytan, E., Ganoth, D., Armon, T. & Hershko, A. ATP-dependent incorporation of 20S protease into the 26S complex that degrades proteins conjugated to ubiquitin. Proc. Natl. Acad. Sci. USA 86, 7751\u20137755 (1989).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"4619_CR24","doi-asserted-by":"publisher","first-page":"6519","DOI":"10.1074\/jbc.274.10.6519","volume":"274","author":"PJ Kallio","year":"1999","unstructured":"Kallio, P. J., Wilson, W. J., O\u2019Brien, S., Makino, Y. & Poellinger, L. Regulation of the hypoxia-inducible transcription factor 1alpha by the ubiquitin-proteasome pathway. J. Biol. Chem. 274, 6519\u20136525 (1999).","journal-title":"J. Biol. Chem."},{"key":"4619_CR25","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1016\/S0092-8674(00)80753-9","volume":"97","author":"DM Koepp","year":"1999","unstructured":"Koepp, D. M., Harper, J. W. & Elledge, S. J. How the cyclin became a cyclin: Regulated proteolysis in the cell cycle. Cell 97, 431\u2013434 (1999).","journal-title":"Cell"},{"key":"4619_CR26","doi-asserted-by":"publisher","first-page":"1194","DOI":"10.1167\/iovs.03-0830","volume":"45","author":"W Guo","year":"2004","unstructured":"Guo, W. et al. Differential regulation of components of the ubiquitin-proteasome pathway during lens cell differentiation. Invest. Ophthalmol. Vis. Sci. 45, 1194\u20131201 (2004).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"4619_CR27","doi-asserted-by":"publisher","first-page":"48228","DOI":"10.1074\/jbc.M304082200","volume":"278","author":"DJ Dupre","year":"2003","unstructured":"Dupre, D. J. et al. Trafficking, ubiquitination, and down-regulation of the human platelet-activating factor receptor. J. Biol. Chem. 278, 48228\u201348235 (2003).","journal-title":"J. Biol. Chem."},{"key":"4619_CR28","first-page":"688","volume":"11","author":"A Shanmugham","year":"2008","unstructured":"Shanmugham, A. & Ovaa, H. DUBs and disease: Activity assays for inhibitor development. Curr. Opin. Drug Discov. Devel. 11, 688\u2013696 (2008).","journal-title":"Curr. Opin. Drug Discov. Devel."},{"key":"4619_CR29","first-page":"255","volume":"3","author":"J Wang","year":"2006","unstructured":"Wang, J. & Maldonado, M. A. The ubiquitin-proteasome system and its role in inflammatory and autoimmune diseases. Cell Mol. Immunol. 3, 255\u2013261 (2006).","journal-title":"Cell Mol. Immunol."},{"key":"4619_CR30","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1182\/asheducation-2007.1.317","volume":"1","author":"P Richardson","year":"2007","unstructured":"Richardson, P., et al. The treatment of relapsed and refractory multiple myeloma. Hematol. Am. Soc. Hematol. Educ. Program. 1, 317\u2013323 (2007).","journal-title":"Hematol. Am. Soc. Hematol. Educ. Program"},{"key":"4619_CR31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1517\/13543784.17.1.1","volume":"17","author":"M Srikanth","year":"2008","unstructured":"Srikanth, M., Davies, F. E. & Morgan, G. J. An update on drug combinations for treatment of myeloma. Expert Opin. Investig. Drugs 17, 1\u201312 (2008).","journal-title":"Expert Opin. Investig. Drugs"},{"key":"4619_CR32","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-018-26532-z","volume":"8","author":"I Gupta","year":"2018","unstructured":"Gupta, I., Aggarwal, S., Singh, K., Yadav, A. & Khan, S. Ubiquitin Proteasome pathway proteins as potential drug targets in parasite Trypanosoma cruzi. Sci. Rep. 8, 1\u201312 (2018).","journal-title":"Sci. Rep."},{"key":"4619_CR33","doi-asserted-by":"publisher","first-page":"487","DOI":"10.3389\/fcimb.2017.00487","volume":"7","author":"J Qiu","year":"2017","unstructured":"Qiu, J. & Luo, Z.-Q. Hijacking of the host ubiquitin network by Legionella pneumophila. Front. Cell. Infect. Microbiol. 7, 487 (2017).","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"4619_CR34","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1038\/nrd.2017.152","volume":"17","author":"JA Harrigan","year":"2018","unstructured":"Harrigan, J. A., Jacq, X., Martin, N. M. & Jackson, S. P. Deubiquitylating enzymes and drug discovery: Emerging opportunities. Nat. Rev. Drug Discov. 17, 57 (2018).","journal-title":"Nat. Rev. Drug Discov."},{"key":"4619_CR35","doi-asserted-by":"publisher","first-page":"e12748","DOI":"10.1111\/cmi.12748","volume":"19","author":"G Datta","year":"2017","unstructured":"Datta, G., Hossain, M. E., Asad, M., Rathore, S. & Mohmmed, A. Plasmodium falciparum OTU-like cysteine protease (PfOTU) is essential for apicoplast homeostasis and associates with noncanonical role of Atg8. Cell. Microbiol. 19, e12748 (2017).","journal-title":"Cell. Microbiol."},{"key":"4619_CR36","doi-asserted-by":"publisher","first-page":"e2335","DOI":"10.1371\/journal.pone.0002335","volume":"3","author":"J Prudhomme","year":"2008","unstructured":"Prudhomme, J. et al. Marine actinomycetes: A new source of compounds against the human malaria parasite. PLoS ONE 3, e2335 (2008).","journal-title":"PLoS ONE"},{"key":"4619_CR37","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1186\/1472-6904-7-13","volume":"7","author":"JM Reynolds","year":"2007","unstructured":"Reynolds, J. M., El Bissati, K., Brandenburg, J., Gunzl, A. & Mamoun, C. B. Antimalarial activity of the anticancer and proteasome inhibitor bortezomib and its analog ZL3B. BMC Clin. Pharmacol. 7, 13 (2007).","journal-title":"BMC Clin. Pharmacol."},{"key":"4619_CR38","doi-asserted-by":"publisher","first-page":"4080","DOI":"10.1128\/AAC.00088-09","volume":"53","author":"B Czesny","year":"2009","unstructured":"Czesny, B., Goshu, S., Cook, J. L. & Williamson, K. C. The proteasome inhibitor epoxomicin has potent Plasmodium falciparum gametocytocidal activity. Antimicrob. Agents Chemother. 53, 4080\u20134085 (2009).","journal-title":"Antimicrob. Agents Chemother."},{"key":"4619_CR39","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1017\/S003118200500747X","volume":"131","author":"C Lindenthal","year":"2005","unstructured":"Lindenthal, C., Weich, N., Chia, Y. S., Heussler, V. & Klinkert, M. Q. The proteasome inhibitor MLN-273 blocks exoerythrocytic and erythrocytic development of Plasmodium parasites. Parasitology 131, 37\u201344 (2005).","journal-title":"Parasitology"},{"key":"4619_CR40","doi-asserted-by":"publisher","first-page":"809","DOI":"10.1016\/j.bbadis.2008.08.010","volume":"1782","author":"MJ Edelmann","year":"2008","unstructured":"Edelmann, M. J. & Kessler, B. M. Ubiquitin and ubiquitin-like specific proteases targeted by infectious pathogens: Emerging patterns and molecular principles. Biochim. Biophys. Acta 1782, 809\u2013816 (2008).","journal-title":"Biochim. Biophys. Acta"},{"key":"4619_CR41","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1111\/j.1365-2958.2007.05753.x","volume":"65","author":"P Hunt","year":"2007","unstructured":"Hunt, P. et al. Gene encoding a deubiquitinating enzyme is mutated in artesunate- and chloroquine-resistant rodent malaria parasites. Mol Microbiol 65, 27\u201340 (2007).","journal-title":"Mol Microbiol"},{"key":"4619_CR42","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1186\/1471-2164-11-499","volume":"11","author":"P Hunt","year":"2010","unstructured":"Hunt, P. et al. Experimental evolution, genetic analysis and genome re-sequencing reveal the mutation conferring artemisinin resistance in an isogenic lineage of malaria parasites. BMC Genom. 11, 499 (2010).","journal-title":"BMC Genom."},{"key":"4619_CR43","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1039\/C3MB70506D","volume":"10","author":"MJ Hamilton","year":"2014","unstructured":"Hamilton, M. J., Lee, M. & Le Roch, K. G. The ubiquitin system: An essential component to unlocking the secrets of malaria parasite biology. Mol. Biosyst. 10, 715\u2013723 (2014).","journal-title":"Mol. Biosyst."},{"key":"4619_CR44","doi-asserted-by":"publisher","first-page":"e2386","DOI":"10.1371\/journal.pone.0002386","volume":"3","author":"N Ponts","year":"2008","unstructured":"Ponts, N. et al. Deciphering the ubiquitin-mediated pathway in apicomplexan parasites: A potential strategy to interfere with parasite virulence. PLoS ONE 3, e2386 (2008).","journal-title":"PLoS ONE"},{"key":"4619_CR45","doi-asserted-by":"publisher","first-page":"17818","DOI":"10.1038\/srep17818","volume":"5","author":"L Wang","year":"2015","unstructured":"Wang, L. et al. Characterization of the 26S proteasome network in Plasmodium falciparum. Sci. Rep. 5, 17818 (2015).","journal-title":"Sci. Rep."},{"key":"4619_CR46","doi-asserted-by":"publisher","first-page":"6857","DOI":"10.1074\/jbc.M109.072405","volume":"285","author":"K Artavanis-Tsakonas","year":"2010","unstructured":"Artavanis-Tsakonas, K. et al. Characterization and structural studies of the Plasmodium falciparum ubiquitin and Nedd8 hydrolase UCHL3. J. Biol. Chem. 285, 6857\u20136866 (2010).","journal-title":"J. Biol. Chem."},{"key":"4619_CR47","doi-asserted-by":"publisher","first-page":"2022","DOI":"10.1002\/jcp.22931","volume":"227","author":"NR Mtango","year":"2012","unstructured":"Mtango, N. R., Sutovsky, M., Vandevoort, C. A., Latham, K. E. & Sutovsky, P. Essential role of ubiquitin C-terminal hydrolases UCHL1 and UCHL3 in mammalian oocyte maturation. J. Cell Physiol. 227, 2022\u20132029 (2012).","journal-title":"J. Cell Physiol."},{"key":"4619_CR48","doi-asserted-by":"publisher","first-page":"3352","DOI":"10.1016\/j.celrep.2018.05.033","volume":"23","author":"C Liao","year":"2018","unstructured":"Liao, C. et al. UCHL3 regulates topoisomerase-induced chromosomal break repair by controlling TDP1 proteostasis. Cell Rep. 23, 3352\u20133365 (2018).","journal-title":"Cell Rep."},{"key":"4619_CR49","doi-asserted-by":"publisher","first-page":"17891","DOI":"10.1038\/s41598-018-36235-0","volume":"8","author":"R Nishi","year":"2018","unstructured":"Nishi, R. et al. The deubiquitylating enzyme UCHL3 regulates Ku80 retention at sites of DNA damage. Sci. Rep. 8, 17891 (2018).","journal-title":"Sci. Rep."},{"key":"4619_CR50","doi-asserted-by":"publisher","first-page":"911","DOI":"10.1016\/j.neuint.2010.03.021","volume":"56","author":"R Setsuie","year":"2010","unstructured":"Setsuie, R., Suzuki, M., Tsuchiya, Y. & Wada, K. Skeletal muscles of Uchl3 knockout mice show polyubiquitinated protein accumulation and stress responses. Neurochem. Int. 56, 911\u2013918 (2010).","journal-title":"Neurochem. Int."},{"key":"4619_CR51","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1038\/s41388-019-0987-z","volume":"39","author":"MH Zhang","year":"2020","unstructured":"Zhang, M. H. et al. UCHL3 promotes ovarian cancer progression by stabilizing TRAF2 to activate the NF-kappaB pathway. Oncogene 39, 322\u2013333 (2020).","journal-title":"Oncogene"},{"key":"4619_CR52","first-page":"556","volume":"50","author":"TT Li","year":"2019","unstructured":"Li, T. T. & Wang, H. J. UCH-L3 expression in epithelial ovarian cancer and its clinical significance. Sichuan Da Xue Xue Bao Yi Xue Ban 50, 556\u2013560 (2019).","journal-title":"Sichuan Da Xue Xue Bao Yi Xue Ban"},{"key":"4619_CR53","first-page":"1970","volume":"9","author":"Z Song","year":"2019","unstructured":"Song, Z. et al. UCHL3 promotes pancreatic cancer progression and chemo-resistance through FOXM1 stabilization. Am. J. Cancer Res. 9, 1970\u20131981 (2019).","journal-title":"Am. J. Cancer Res."},{"key":"4619_CR54","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1134\/S1607672914030107","volume":"456","author":"EV Filatova","year":"2014","unstructured":"Filatova, E. V. et al. Expression analysis of genes of ubiquitin-proteasome protein degradation system in MPTP-induced mice models of early stages of Parkinson\u2019s disease. Dokl. Biochem. Biophys. 456, 116\u2013118 (2014).","journal-title":"Dokl. Biochem. Biophys."},{"key":"4619_CR55","doi-asserted-by":"publisher","first-page":"3593","DOI":"10.1074\/jbc.M807172200","volume":"284","author":"MW Popp","year":"2009","unstructured":"Popp, M. W., Artavanis-Tsakonas, K. & Ploegh, H. L. Substrate filtering by the active site crossover loop in UCHL3 revealed by sortagging and gain-of-function mutations. J. Biol. Chem. 284, 3593\u20133602 (2009).","journal-title":"J. Biol. Chem."},{"key":"4619_CR56","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1038\/nature16936","volume":"530","author":"H Li","year":"2016","unstructured":"Li, H. et al. Structure- and function-based design of Plasmodium-selective proteasome inhibitors. Nature 530, 233\u2013236 (2016).","journal-title":"Nature"},{"key":"4619_CR57","doi-asserted-by":"publisher","first-page":"33054","DOI":"10.1074\/jbc.M110.162081","volume":"285","author":"ML Booker","year":"2010","unstructured":"Booker, M. L. et al. Novel inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase with anti-malarial activity in the mouse model. J. Biol. Chem. 285, 33054\u201333064 (2010).","journal-title":"J. Biol. Chem."},{"key":"4619_CR58","doi-asserted-by":"publisher","first-page":"6023","DOI":"10.1128\/AAC.00914-16","volume":"60","author":"MI Davis","year":"2016","unstructured":"Davis, M. I. et al. Identification of novel Plasmodium falciparum hexokinase inhibitors with antiparasitic activity. Antimicrob. Agents Chemother. 60, 6023\u20136033 (2016).","journal-title":"Antimicrob. Agents Chemother."},{"key":"4619_CR59","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1007\/978-3-319-67144-4_14","volume":"1031","author":"BA Austin","year":"2017","unstructured":"Austin, B. A. & Gadhia, A. D. New therapeutic uses for existing drugs. Adv. Exp. Med. Biol. 1031, 233\u2013247 (2017).","journal-title":"Adv. Exp. Med. Biol."},{"key":"4619_CR60","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/nrd.2018.92","volume":"18","author":"A Breckenridge","year":"2019","unstructured":"Breckenridge, A. & Jacob, R. Overcoming the legal and regulatory barriers to drug repurposing. Nat. Rev. Drug. Discov. 18, 1\u20132 (2019).","journal-title":"Nat. Rev. Drug. Discov."},{"key":"4619_CR61","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1038\/nrd1468","volume":"3","author":"TT Ashburn","year":"2004","unstructured":"Ashburn, T. T. & Thor, K. B. Drug repositioning: Identifying and developing new uses for existing drugs. Nat. Rev. Drug. Discov. 3, 673\u2013683 (2004).","journal-title":"Nat. Rev. Drug. Discov."},{"key":"4619_CR62","doi-asserted-by":"publisher","first-page":"2037","DOI":"10.1039\/C8MD00319J","volume":"9","author":"CGL Veale","year":"2018","unstructured":"Veale, C. G. L. & Hoppe, H. C. Screening of the Pathogen Box reveals new starting points for anti-trypanosomal drug discovery. Medchemcomm 9, 2037\u20132044 (2018).","journal-title":"Medchemcomm"},{"key":"4619_CR63","doi-asserted-by":"publisher","first-page":"1941","DOI":"10.3389\/fmicb.2019.01941","volume":"10","author":"I Dandachi","year":"2019","unstructured":"Dandachi, I., Chaddad, A., Hanna, J., Matta, J. & Daoud, Z. Understanding the epidemiology of multi-drug resistant gram-negative bacilli in the middle east using a one health approach. Front. Microbiol. 10, 1941 (2019).","journal-title":"Front. Microbiol."},{"key":"4619_CR64","doi-asserted-by":"publisher","first-page":"471","DOI":"10.3390\/genes10060471","volume":"10","author":"X Wang","year":"2019","unstructured":"Wang, X., et al. Identification of Plasmodium falciparum mitochondrial malate: Quinone oxidoreductase inhibitors from the pathogen box. Genes (Basel). 10, 471 (2019).","journal-title":"Genes (Basel)"},{"key":"4619_CR65","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1016\/j.ijpara.2020.01.002","volume":"50","author":"MG Dans","year":"2020","unstructured":"Dans, M. G. et al. Screening the Medicines for Malaria Venture Pathogen Box for invasion and egress inhibitors of the blood stage of Plasmodium falciparum reveals several inhibitory compounds. Int. J. Parasitol. 50, 235\u2013252 (2020).","journal-title":"Int. J. Parasitol."},{"key":"4619_CR66","doi-asserted-by":"publisher","first-page":"e01640-17","DOI":"10.1128\/AAC.01640-17","volume":"62","author":"J Spalenka","year":"2018","unstructured":"Spalenka, J., et al. Discovery of new inhibitors of toxoplasma gondii via the Pathogen Box. Antimicrob. Agents Chemother. 62, e01640\u201317 (2018).","journal-title":"Antimicrob. Agents Chemother"},{"key":"4619_CR67","doi-asserted-by":"publisher","first-page":"e00120-17","DOI":"10.1128\/mSphere.00120-17","volume":"2","author":"FL Mayer","year":"2010","unstructured":"Mayer, F.L. & Kronstad, J.W. Discovery of a novel antifungal agent in the Pathogen Box. mSphere 2, e00120\u201317 (2017).","journal-title":"mSphere"},{"key":"4619_CR68","doi-asserted-by":"publisher","first-page":"2719","DOI":"10.1021\/jm901137j","volume":"53","author":"JB Baell","year":"2010","unstructured":"Baell, J. B. & Holloway, G. A. New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. J. Med. Chem. 53, 2719\u20132740 (2010).","journal-title":"J. Med. Chem."},{"key":"4619_CR69","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1016\/j.cell.2016.07.055","volume":"167","author":"AF Cowman","year":"2016","unstructured":"Cowman, A. F., Healer, J., Marapana, D. & Marsh, K. Malaria: Biology and disease. Cell 167, 610\u2013624 (2016).","journal-title":"Cell"},{"key":"4619_CR70","doi-asserted-by":"publisher","first-page":"723","DOI":"10.1016\/S0140-6736(13)60024-0","volume":"383","author":"NJ White","year":"2014","unstructured":"White, N. J. et al. Malaria. Lancet 383, 723\u2013735 (2014).","journal-title":"Lancet"},{"key":"4619_CR71","doi-asserted-by":"publisher","first-page":"17050","DOI":"10.1038\/nrdp.2017.50","volume":"3","author":"MA Phillips","year":"2017","unstructured":"Phillips, M. A. et al. Malaria. Nat. Rev. Dis. Primers 3, 17050 (2017).","journal-title":"Nat. Rev. Dis. Primers"},{"key":"4619_CR72","doi-asserted-by":"publisher","first-page":"1191","DOI":"10.1517\/13543776.2015.1056737","volume":"25","author":"P Farshi","year":"2015","unstructured":"Farshi, P. et al. Deubiquitinases (DUBs) and DUB inhibitors: A patent review. Expert Opin. Ther. Pat. 25, 1191\u20131208 (2015).","journal-title":"Expert Opin. Ther. Pat."},{"key":"4619_CR73","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.compbiolchem.2013.04.002","volume":"45","author":"J Franco","year":"2013","unstructured":"Franco, J. et al. A structural comparative approach to identifying novel antimalarial inhibitors. Comput. Biol. Chem. 45, 42\u201347 (2013).","journal-title":"Comput. Biol. Chem."},{"key":"4619_CR74","doi-asserted-by":"publisher","first-page":"2344","DOI":"10.1021\/ci9002393","volume":"49","author":"P Zhou","year":"2009","unstructured":"Zhou, P., Zou, J., Tian, F. & Shang, Z. Fluorine bonding how does it work in protein\u2013ligand interactions?. J. Chem. Inf. Model. 49, 2344\u20132355 (2009).","journal-title":"J. Chem. Inf. Model."},{"key":"4619_CR75","doi-asserted-by":"publisher","first-page":"1616","DOI":"10.1128\/AAC.01676-09","volume":"54","author":"MR Pasca","year":"2010","unstructured":"Pasca, M. R. et al. Clinical isolates of Mycobacterium tuberculosis in four European hospitals are uniformly susceptible to benzothiazinones. Antimicrob. Agents Chemother. 54, 1616\u20131618 (2010).","journal-title":"Antimicrob. Agents Chemother."},{"key":"4619_CR76","doi-asserted-by":"publisher","first-page":"29717","DOI":"10.1038\/srep29717","volume":"6","author":"C Gao","year":"2016","unstructured":"Gao, C. et al. Benzothiazinethione is a potent preclinical candidate for the treatment of drug-resistant tuberculosis. Sci. Rep. 6, 29717 (2016).","journal-title":"Sci. Rep."},{"key":"4619_CR77","doi-asserted-by":"publisher","first-page":"3984","DOI":"10.1128\/AAC.00115-12","volume":"56","author":"L Vera-Cabrera","year":"2012","unstructured":"Vera-Cabrera, L., Campos-Rivera, M. P., Gonzalez-Martinez, N. A., Ocampo-Candiani, J. & Cole, S. T. In vitro activities of the new antitubercular agents PA-824 and BTZ043 against Nocardia brasiliensis. Antimicrob. Agents Chemother. 56, 3984\u20133985 (2012).","journal-title":"Antimicrob. Agents Chemother."},{"key":"4619_CR78","doi-asserted-by":"publisher","first-page":"6177","DOI":"10.1074\/jbc.M113.522623","volume":"289","author":"S Grover","year":"2014","unstructured":"Grover, S. et al. Benzothiazinones mediate killing of Corynebacterineae by blocking decaprenyl phosphate recycling involved in cell wall biosynthesis. J. Biol. Chem. 289, 6177\u20136187 (2014).","journal-title":"J. Biol. Chem."},{"key":"4619_CR79","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1126\/science.1171583","volume":"324","author":"V Makarov","year":"2009","unstructured":"Makarov, V. et al. Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis. Science 324, 801\u2013804 (2009).","journal-title":"Science"},{"key":"4619_CR80","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1021\/jm701052u","volume":"51","author":"A Gangjee","year":"2008","unstructured":"Gangjee, A., Li, W., Yang, J. & Kisliuk, R. L. Design, synthesis, and biological evaluation of classical and nonclassical 2-amino-4-oxo-5-substituted-6-methylpyrrolo[3,2-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors. J. Med. Chem. 51, 68\u201376 (2008).","journal-title":"J. Med. Chem."},{"key":"4619_CR81","doi-asserted-by":"publisher","first-page":"905","DOI":"10.1038\/nprot.2016.051","volume":"11","author":"S Forli","year":"2016","unstructured":"Forli, S. et al. Computational protein-ligand docking and virtual drug screening with the AutoDock suite. Nat. Protoc. 11, 905\u2013919 (2016).","journal-title":"Nat. Protoc."},{"key":"4619_CR82","doi-asserted-by":"publisher","first-page":"42717","DOI":"10.1038\/srep42717","volume":"7","author":"A Daina","year":"2017","unstructured":"Daina, A., Michielin, O. & Zoete, V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep. 7, 42717 (2017).","journal-title":"Sci. Rep."},{"key":"4619_CR83","doi-asserted-by":"publisher","first-page":"13773","DOI":"10.1039\/C8NR02442A","volume":"10","author":"M Raza","year":"2018","unstructured":"Raza, M., Bharti, H., Singal, A., Nag, A. & Ghosh, P. C. Long circulatory liposomal maduramicin inhibits the growth of Plasmodium falciparum blood stages in culture and cures murine models of experimental malaria. Nanoscale 10, 13773\u201313791 (2018).","journal-title":"Nanoscale"},{"key":"4619_CR84","doi-asserted-by":"publisher","first-page":"418","DOI":"10.2307\/3280287","volume":"65","author":"C Lambros","year":"1979","unstructured":"Lambros, C. & Vanderberg, J.P. Synchronization of Plasmodium falciparum erythrocytic stages in culture. J. Parasitol. 65, 418\u2013420 (1979).","journal-title":"J. Parasitol"},{"key":"4619_CR85","doi-asserted-by":"publisher","first-page":"1803","DOI":"10.1128\/AAC.48.5.1803-1806.2004","volume":"48","author":"M Smilkstein","year":"2004","unstructured":"Smilkstein, M., Sriwilaijaroen, N., Kelly, J. X., Wilairat, P. & Riscoe, M. Simple and inexpensive fluorescence-based technique for high-throughput antimalarial drug screening. Antimicrob. Agents Chemother. 48, 1803\u20131806 (2004).","journal-title":"Antimicrob. Agents Chemother."},{"key":"4619_CR86","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1006\/expr.1993.1010","volume":"76","author":"F Terkuile","year":"1993","unstructured":"Terkuile, F., White, N., Holloway, P., Pasvol, G. & Krishna, S. Plasmodium falciparum: In vitro studies of the pharmacodynamic properties of drugs used for the treatment of severe malaria. Exp. Parasitol. 76, 85\u201395 (1993).","journal-title":"Exp. Parasitol."},{"key":"4619_CR87","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1016\/j.jddst.2015.08.009","volume":"29","author":"M Pachauri","year":"2015","unstructured":"Pachauri, M., Gupta, E. D. & Ghosh, P. C. Piperine loaded PEG-PLGA nanoparticles: Preparation, characterization and targeted delivery for adjuvant breast cancer chemotherapy. J. Drug Deliv. Sci. Technol. 29, 269\u2013282 (2015).","journal-title":"J. Drug Deliv. Sci. Technol."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-04619-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-04619-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-04619-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,24]],"date-time":"2022-11-24T22:30:32Z","timestamp":1669329032000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-04619-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,18]]},"references-count":87,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["4619"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-04619-4","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,18]]},"assertion":[{"value":"18 March 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 December 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 January 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"918"}}