{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,19]],"date-time":"2026-07-19T01:15:36Z","timestamp":1784423736848,"version":"3.55.0"},"reference-count":72,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,6,18]],"date-time":"2022-06-18T00:00:00Z","timestamp":1655510400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["1R01AI159450"],"award-info":[{"award-number":["1R01AI159450"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>The current treatments for lymphatic filariasis and onchocerciasis do not effectively kill the adult parasitic nematodes, allowing these chronic and debilitating diseases to persist in millions of people. Thus, the discovery of new drugs with macrofilaricidal potential to treat these filarial diseases is critical. To facilitate this need, we first investigated the effects of three aspartyl protease inhibitors (APIs) that are FDA-approved as HIV antiretroviral drugs on the adult filarial nematode, Brugia malayi and the endosymbiotic bacteria, Wolbachia. From the three hits, nelfinavir had the best potency with an IC50 value of 7.78 \u00b5M, followed by ritonavir and lopinavir with IC50 values of 14.3 \u00b5M and 16.9 \u00b5M, respectively. The three APIs have a direct effect on killing adult B. malayi after 6 days of exposure in vitro and did not affect the Wolbachia titers. Sequence conservation and stage-specific gene expression analysis identified Bm8660 as the most likely primary aspartic protease target for these drug(s). Immunolocalization using antibodies raised against the Bm8660 ortholog of Onchocerca volvulus showed it is strongly expressed in female B. malayi, especially in metabolically active tissues such as lateral and dorsal\/ventral chords, hypodermis, and uterus tissue. Global transcriptional response analysis using adult female B. pahangi treated with APIs identified four additional aspartic proteases differentially regulated by the three effective drugs, as well as significant enrichment of various pathways including ubiquitin mediated proteolysis, protein kinases, and MAPK\/AMPK\/FoxO signaling. In vitro testing against the adult gastro-intestinal nematode Trichuris muris suggested broad-spectrum potential for these APIs. This study suggests that APIs may serve as new leads to be further explored for drug discovery to treat parasitic nematode infections.<\/jats:p>","DOI":"10.3390\/pathogens11060707","type":"journal-article","created":{"date-parts":[[2022,6,19]],"date-time":"2022-06-19T21:19:26Z","timestamp":1655673566000},"page":"707","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Aspartyl Protease Inhibitors as Anti-Filarial Drugs"],"prefix":"10.3390","volume":"11","author":[{"given":"Liana","family":"Beld","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1083-2882","authenticated-orcid":false,"given":"Hyeim","family":"Jung","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina A.","family":"Bulman","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6820-446X","authenticated-orcid":false,"given":"Bruce A.","family":"Rosa","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4558-3417","authenticated-orcid":false,"given":"Peter U.","family":"Fischer","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James W.","family":"Janetka","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2389-6113","authenticated-orcid":false,"given":"Sara","family":"Lustigman","sequence":"additional","affiliation":[{"name":"Molecular Parasitology, New York Blood Center, Lindsley F. Kimball Research Institute, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judy A.","family":"Sakanari","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9572-3436","authenticated-orcid":false,"given":"Makedonka","family":"Mitreva","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA"},{"name":"McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Mitra, A.K., and Mawson, A.R. (2017). Neglected Tropical Diseases: Epidemiology and Global Burden. Trop. Med. Infect. Dis., 2.","DOI":"10.3390\/tropicalmed2030036"},{"key":"ref_2","unstructured":"WHO Lymphatic Filariasis. World Health Organization Fact Sheets, WHO. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/lymphatic-filariasis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1016\/S0140-6736(10)60586-7","article-title":"Lymphatic filariasis and onchocerciasis","volume":"376","author":"Taylor","year":"2010","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1801","DOI":"10.1056\/NEJMoa1706854","article-title":"A Trial of a Triple-Drug Treatment for Lymphatic Filariasis","volume":"379","author":"King","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"706","DOI":"10.4103\/ijmr.IJMR_454_17","article-title":"Anti-Wolbachia therapy for onchocerciasis & lymphatic filariasis: Current perspectives","volume":"149","author":"Mohamed","year":"2019","journal-title":"Indian J. Med. Res."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Ottesen, E.A., Hooper, P.J., Bradley, M., and Biswas, G. (2008). The global programme to eliminate lymphatic filariasis: Health impact after 8 years. PLoS Negl. Trop. Dis., 2.","DOI":"10.1371\/journal.pntd.0000317"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1097\/00001432-200104000-00008","article-title":"Current status and future prospects of the Global Lymphatic Filariasis Programme","volume":"14","author":"Molyneux","year":"2001","journal-title":"Curr. Opin. Infect. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e1186","DOI":"10.1016\/S2214-109X(20)30286-2","article-title":"The global distribution of lymphatic filariasis, 2000\u20132018: A geospatial analysis","volume":"8","year":"2020","journal-title":"Lancet Glob. Health"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2561","DOI":"10.1093\/cid\/ciz671","article-title":"The Health and Economic Burdens of Lymphatic Filariasis Prior to Mass Drug Administration Programs","volume":"70","author":"Mathew","year":"2020","journal-title":"Clin. Infect. Dis."},{"key":"ref_10","unstructured":"Newman, T.E., and Juergens, A.L. (2022). Filariasis. StatPearls, StatPearls."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Grote, A., Voronin, D., Ding, T., Twaddle, A., Unnasch, T.R., Lustigman, S., and Ghedin, E. (2017). Defining Brugia malayi and Wolbachia symbiosis by stage-specific dual RNA-seq. PLoS Negl. Trop. Dis., 11.","DOI":"10.1371\/journal.pntd.0005357"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1099\/mic.0.000724","article-title":"Microbe Profile: Wolbachia: A sex selector, a viral protector and a target to treat filarial nematodes","volume":"164","author":"Taylor","year":"2018","journal-title":"Microbiology"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Tyagi, R., Bulman, C.A., Cho-Ngwa, F., Fischer, C., Marcellino, C., Arkin, M.R., McKerrow, J.H., McNamara, C.W., Mahoney, M., and Tricoche, N. (2021). An Integrated Approach to Identify New Anti-Filarial Leads to Treat River Blindness, a Neglected Tropical Disease. Pathogens, 10.","DOI":"10.3390\/pathogens10010071"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/j.jsps.2021.04.004","article-title":"Anthelmintics for drug repurposing: Opportunities and challenges","volume":"29","author":"Alavi","year":"2021","journal-title":"Saudi Pharm. J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"10750","DOI":"10.1073\/pnas.1810137115","article-title":"The ReFRAME library as a comprehensive drug repurposing library and its application to the treatment of cryptosporidiosis","volume":"115","author":"Janes","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.ijpddr.2014.07.002","article-title":"Repurposing drugs for the treatment and control of helminth infections","volume":"4","author":"Panic","year":"2014","journal-title":"Int. J. Parasitol. Drugs Drug Resist."},{"key":"ref_17","first-page":"95","article-title":"HIV protease inhibitors: A review of molecular selectivity and toxicity","volume":"7","author":"Lv","year":"2015","journal-title":"HIV\/AIDS-Res. Palliat. Care"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"30433","DOI":"10.1074\/jbc.R800035200","article-title":"Proteases: Multifunctional enzymes in life and disease","volume":"283","author":"Bond","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/nrd.2016.230","article-title":"A comprehensive map of molecular drug targets","volume":"16","author":"Santos","year":"2017","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1038\/s41588-018-0262-1","article-title":"Comparative genomics of the major parasitic worms","volume":"51","year":"2019","journal-title":"Nat. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Donohue, R.E., Cross, Z.K., and Michael, E. (2019). The extent, nature, and pathogenic consequences of helminth polyparasitism in humans: A meta-analysis. PLoS Negl. Trop. Dis., 13.","DOI":"10.1371\/journal.pntd.0007455"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Bulman, C.A., Bidlow, C.M., Lustigman, S., Cho-Ngwa, F., Williams, D., Rascon, A.A., Tricoche, N., Samje, M., Bell, A., and Suzuki, B. (2015). Repurposing auranofin as a lead candidate for treatment of lymphatic filariasis and onchocerciasis. PLoS Negl. Trop. Dis., 9.","DOI":"10.1371\/journal.pntd.0003534"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Marcellino, C., Gut, J., Lim, K.C., Singh, R., McKerrow, J., and Sakanari, J. (2012). WormAssay: A novel computer application for whole-plate motion-based screening of macroscopic parasites. PLoS Negl. Trop. Dis., 6.","DOI":"10.1371\/journal.pntd.0001494"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Jasmer, D.P., Rosa, B.A., Tyagi, R., Bulman, C.A., Beerntsen, B., Urban, J.F., Sakanari, J., and Mitreva, M. (2020). De novo identification of toxicants that cause irreparable damage to parasitic nematode intestinal cells. PLoS Negl. Trop. Dis., 14.","DOI":"10.1371\/journal.pntd.0007942"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.molbiopara.2004.01.006","article-title":"Population dynamics of Wolbachia bacterial endosymbionts in Brugia malayi","volume":"135","author":"McGarry","year":"2004","journal-title":"Mol. Biochem. Parasitol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Gunderson, E.L., Vogel, I., Chappell, L., Bulman, C.A., Lim, K.C., Luo, M., Whitman, J.D., Franklin, C., Choi, Y.J., and Lefoulon, E. (2020). The endosymbiont Wolbachia rebounds following antibiotic treatment. PLoS Pathog., 16.","DOI":"10.1371\/journal.ppat.1008623"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.molbiopara.2016.11.005","article-title":"WormBase ParaSite\u2014A comprehensive resource for helminth genomics","volume":"215","author":"Howe","year":"2017","journal-title":"Mol. Biochem. Parasitol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"D884","DOI":"10.1093\/nar\/gkaa942","article-title":"Ensembl 2021","volume":"49","author":"Howe","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"D624","DOI":"10.1093\/nar\/gkx1134","article-title":"The MEROPS database of proteolytic enzymes, their substrates and inhibitors in 2017 and a comparison with peptidases in the PANTHER database","volume":"46","author":"Rawlings","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1006\/jmbi.2000.4042","article-title":"T-Coffee: A novel method for fast and accurate multiple sequence alignment","volume":"302","author":"Notredame","year":"2000","journal-title":"J. Mol. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1038\/msb.2011.75","article-title":"Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega","volume":"7","author":"Sievers","year":"2011","journal-title":"Mol. Syst. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1186\/s13059-019-1832-y","article-title":"OrthoFinder: Phylogenetic orthology inference for comparative genomics","volume":"20","author":"Emms","year":"2019","journal-title":"Genome Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1093\/bib\/bbx108","article-title":"MAFFT online service: Multiple sequence alignment, interactive sequence choice and visualization","volume":"20","author":"Katoh","year":"2019","journal-title":"Brief. Bioinform."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1093\/bioinformatics\/btp033","article-title":"Jalview Version 2--a multiple sequence alignment editor and analysis workbench","volume":"25","author":"Waterhouse","year":"2009","journal-title":"Bioinformatics"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1038\/s41592-021-01101-x","article-title":"Sensitive protein alignments at tree-of-life scale using DIAMOND","volume":"18","author":"Buchfink","year":"2021","journal-title":"Nat. Methods"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"bar030","DOI":"10.1093\/database\/bar030","article-title":"Ensembl BioMarts: A hub for data retrieval across taxonomic space","volume":"2011","author":"Kinsella","year":"2011","journal-title":"Database"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.exppara.2004.06.006","article-title":"Onchocerca volvulus: Expression and immunolocalization of a nematode cathepsin D-like lysosomal aspartic protease","volume":"107","author":"Jolodar","year":"2004","journal-title":"Exp. Parasitol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Fischer, K., Beatty, W.L., Jiang, D., Weil, G.J., and Fischer, P.U. (2011). Tissue and stage-specific distribution of Wolbachia in Brugia malayi. PLoS Negl. Trop. Dis., 5.","DOI":"10.1371\/journal.pntd.0001174"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Fischer, K., Beatty, W.L., Weil, G.J., and Fischer, P.U. (2014). High pressure freezing\/freeze substitution fixation improves the ultrastructural assessment of Wolbachia endosymbiont-filarial nematode host interaction. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0086383"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: Ultrafast universal RNA-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1093\/bioinformatics\/btt656","article-title":"featureCounts: An efficient general purpose program for assigning sequence reads to genomic features","volume":"30","author":"Liao","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"R106","DOI":"10.1186\/gb-2010-11-10-r106","article-title":"Differential expression analysis for sequence count data","volume":"11","author":"Anders","year":"2010","journal-title":"Genome Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"D19","DOI":"10.1093\/nar\/gkq1019","article-title":"The Sequence Read Archive","volume":"39","author":"Leinonen","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Choi, Y.J., Ghedin, E., Berriman, M., McQuillan, J., Holroyd, N., Mayhew, G.F., Christensen, B.M., and Michalski, M.L. (2011). A deep sequencing approach to comparatively analyze the transcriptome of lifecycle stages of the filarial worm, Brugia malayi. PLoS Negl. Trop. Dis., 5.","DOI":"10.1371\/journal.pntd.0001409"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1038\/ng.3010","article-title":"Whipworm genome and dual-species transcriptome analyses provide molecular insights into an intimate host-parasite interaction","volume":"46","author":"Foth","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1093\/bioinformatics\/btu031","article-title":"InterProScan 5: Genome-scale protein function classification","volume":"30","author":"Jones","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"D325","DOI":"10.1093\/nar\/gkaa1113","article-title":"The Gene Ontology resource: Enriching a GOld mine","volume":"49","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"D344","DOI":"10.1093\/nar\/gkaa977","article-title":"The InterPro protein families and domains database: 20 years on","volume":"49","author":"Blum","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1016\/j.jmb.2015.11.006","article-title":"BlastKOALA and GhostKOALA: KEGG Tools for Functional Characterization of Genome and Metagenome Sequences","volume":"428","author":"Kanehisa","year":"2016","journal-title":"J. Mol. Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"D545","DOI":"10.1093\/nar\/gkaa970","article-title":"KEGG: Integrating viruses and cellular organisms","volume":"49","author":"Kanehisa","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"W199","DOI":"10.1093\/nar\/gkz401","article-title":"WebGestalt 2019: Gene set analysis toolkit with revamped UIs and APIs","volume":"47","author":"Liao","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1172\/JCI4768","article-title":"Tetracycline therapy targets intracellular bacteria in the filarial nematode Litomosoides sigmodontis and results in filarial infertility","volume":"103","author":"Hoerauf","year":"1999","journal-title":"J. Clin. Invest."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"31504","DOI":"10.1074\/jbc.M704273200","article-title":"Presenilin 1 regulates epidermal growth factor receptor turnover and signaling in the endosomal-lysosomal pathway","volume":"282","author":"Repetto","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"109775","DOI":"10.1016\/j.cellsig.2020.109775","article-title":"Nelfinavir inhibits human DDI2 and potentiates cytotoxicity of proteasome inhibitors","volume":"75","author":"Gu","year":"2020","journal-title":"Cell Signal."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1182\/bloodadvances.2020003820","article-title":"Multiple myeloma cells depend on the DDI2\/NRF1-mediated proteasome stress response for survival","volume":"6","author":"Chen","year":"2022","journal-title":"Blood Adv."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"126","DOI":"10.3389\/fncel.2018.00126","article-title":"Interplay Between the Autophagy-Lysosomal Pathway and the Ubiquitin-Proteasome System: A Target for Therapeutic Development in Alzheimer\u2019s Disease","volume":"12","author":"Bustamante","year":"2018","journal-title":"Front. Cell. Neurosci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"226","DOI":"10.4161\/cbt.8.3.7339","article-title":"Nelfinavir induces the unfolded protein response in ovarian cancer cells, resulting in ER vacuolization, cell cycle retardation and apoptosis","volume":"8","author":"Bruning","year":"2009","journal-title":"Cancer Biol. Ther."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1883","DOI":"10.1158\/1078-0432.CCR-05-1167","article-title":"Effects of HIV protease inhibitor ritonavir on Akt-regulated cell proliferation in breast cancer","volume":"12","author":"Srirangam","year":"2006","journal-title":"Clin. Cancer Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1124\/mol.105.012898","article-title":"HIV protease inhibitors activate the unfolded protein response in macrophages: Implication for atherosclerosis and cardiovascular disease","volume":"68","author":"Zhou","year":"2005","journal-title":"Mol. Pharmacol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2595","DOI":"10.1097\/00002030-199912240-00016","article-title":"The HIV protease inhibitors saquinavir, ritonavir, and nelfinavir but not indinavir impair the epithelial barrier in the human intestinal cell line HT-29\/B6","volume":"13","author":"Bode","year":"1999","journal-title":"AIDS"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1111\/j.1749-6632.2000.tb05233.x","article-title":"Effects of HIV protease inhibitors on barrier function in the human intestinal cell line HT-29\/B6","volume":"915","author":"Bode","year":"2000","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1177\/135965350501000506","article-title":"The HIV protease inhibitors saquinavir, ritonavir, and nelfinavir induce apoptosis and decrease barrier function in human intestinal epithelial cells","volume":"10","author":"Bode","year":"2005","journal-title":"Antivir. Ther."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"G1071","DOI":"10.1152\/ajpgi.00182.2006","article-title":"HIV protease inhibitors activate the unfolded protein response and disrupt lipid metabolism in primary hepatocytes","volume":"291","author":"Zhou","year":"2006","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.1016\/j.bbamcr.2010.12.012","article-title":"The MAPK cascades: Signaling components, nuclear roles and mechanisms of nuclear translocation","volume":"1813","author":"Plotnikov","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.ijpddr.2014.08.001","article-title":"Potential involvement of Brugia malayi cysteine proteases in the maintenance of the endosymbiotic relationship with Wolbachia","volume":"4","author":"Lustigman","year":"2014","journal-title":"Int. J. Parasitol. Drugs Drug Resist."},{"key":"ref_66","unstructured":"CDC (2020, November 08). DPDx\u2014Laboratory Identification of Parasites of Public Health Concern: Lymphatic Filariasis, Available online: https:\/\/www.cdc.gov\/dpdx\/lymphaticfilariasis\/index.html."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"6986","DOI":"10.1128\/IAI.71.12.6986-6994.2003","article-title":"Removal of Wolbachia from Brugia pahangi is closely linked to worm death and fecundity but does not result in altered lymphatic lesion formation in Mongolian gerbils (Meriones unguiculatus)","volume":"71","author":"Chirgwin","year":"2003","journal-title":"Infect. Immun."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2484","DOI":"10.1073\/pnas.92.7.2484","article-title":"ABT-538 is a potent inhibitor of human immunodeficiency virus protease and has high oral bioavailability in humans","volume":"92","author":"Kempf","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1593\/neo.13276","article-title":"Targeting cathepsin E in pancreatic cancer by a small molecule allows in vivo detection","volume":"15","author":"Keliher","year":"2013","journal-title":"Neoplasia"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Fassmannova, D., Sedlak, F., Sedlacek, J., Spicka, I., and Grantz Saskova, K. (2020). Nelfinavir Inhibits the TCF11\/Nrf1-Mediated Proteasome Recovery Pathway in Multiple Myeloma. Cancers, 12.","DOI":"10.3390\/cancers12051065"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"761","DOI":"10.2147\/OTT.S79776","article-title":"The human immunodeficiency virus protease inhibitor ritonavir is potentially active against urological malignancies","volume":"8","author":"Sato","year":"2015","journal-title":"Onco Targets Ther."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.exppara.2008.09.020","article-title":"Brugia malayi: Effects of nitazoxanide and tizoxanide on adult worms and microfilariae of filarial nematodes","volume":"121","author":"Rao","year":"2009","journal-title":"Exp. Parasitol."}],"container-title":["Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-0817\/11\/6\/707\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:34:45Z","timestamp":1760139285000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-0817\/11\/6\/707"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,18]]},"references-count":72,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["pathogens11060707"],"URL":"https:\/\/doi.org\/10.3390\/pathogens11060707","relation":{},"ISSN":["2076-0817"],"issn-type":[{"value":"2076-0817","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,18]]}}}