{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T11:19:45Z","timestamp":1773659985550,"version":"3.50.1"},"reference-count":54,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,5,26]],"date-time":"2021-05-26T00:00:00Z","timestamp":1621987200000},"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":["1R21AI137721"],"award-info":[{"award-number":["1R21AI137721"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"name":"State of Florida, Department of Health","award":["Florida Drug Discovery Acceleration Program"],"award-info":[{"award-number":["Florida Drug Discovery Acceleration Program"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Specific adhesion of P. falciparum parasite-infected erythrocytes (IE) in deep vascular beds can result in severe complications, such as cerebral malaria, placental malaria, respiratory distress, and severe anemia. Cerebral malaria and severe malaria syndromes were associated previously with sequestration of IE to a microvasculature receptor ICAM-1. The screening of Torrey Pines Scaffold Ranking library, which consists of more than 30 million compounds designed around 75 molecular scaffolds, identified small molecules that inhibit cytoadhesion of ICAM-1-binding IE to surface-immobilized receptor at IC50 range down to ~350 nM. With their low cytotoxicity toward erythrocytes and human endothelial cells, these molecules might be suitable for development into potentially effective adjunct anti-adhesion drugs to treat cerebral and\/or severe malaria syndromes. Our two-step high-throughput screening approach is specifically designed to work with compound mixtures to make screening and deconvolution to single active compounds fast and efficient.<\/jats:p>","DOI":"10.3390\/ijms22115659","type":"journal-article","created":{"date-parts":[[2021,5,26]],"date-time":"2021-05-26T10:30:32Z","timestamp":1622025032000},"page":"5659","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Small Molecule Compounds Identified from Mixture-Based Library Inhibit Binding between Plasmodium falciparum Infected Erythrocytes and Endothelial Receptor ICAM-1"],"prefix":"10.3390","volume":"22","author":[{"given":"Olga","family":"Chesnokov","sequence":"first","affiliation":[{"name":"Charles E. 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Parasitol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1172\/JCI114234","article-title":"A human 88-kD membrane glycoprotein (CD36) functions in vitro as a receptor for a cytoadherence ligand on Plasmodium falciparum-infected erythrocytes","volume":"84","author":"Barnwell","year":"1989","journal-title":"J. Clin. Investig."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/341057a0","article-title":"Intercellular adhesion molecule-1 is an endothelial cell adhesion receptor for Plasmodium falciparum","volume":"341","author":"Berendt","year":"1989","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1042\/bst0270487","article-title":"Role of glycans in Plasmodium falciparum infection","volume":"27","author":"Barragan","year":"1999","journal-title":"Biochem. Soc. Trans."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1502","DOI":"10.1126\/science.272.5267.1502","article-title":"Adherence of Plasmodium falciparum to chondroitin sulfate A in the human placenta","volume":"272","author":"Fried","year":"1996","journal-title":"Science"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1878","DOI":"10.1126\/science.8009217","article-title":"Malaria pathogenesis","volume":"264","author":"Miller","year":"1994","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"389","DOI":"10.4269\/ajtmh.1997.57.389","article-title":"Receptor-specific adhesion and clinical disease in Plasmodium falciparum","volume":"57","author":"Newbold","year":"1997","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_10","first-page":"1057","article-title":"An immunohistochemical study of the pathology of fatal malaria. Evidence for widespread endothelial activation and a potential role for intercellular adhesion molecule-1 in cerebral sequestration","volume":"145","author":"Turner","year":"1994","journal-title":"Am. J. Pathol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1016\/S1471-4922(02)02353-X","article-title":"Breaking down the blood-brain barrier: Signaling a path to cerebral malaria?","volume":"18","author":"Adams","year":"2002","journal-title":"Trends Parasitol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.chom.2017.02.009","article-title":"Structure-Guided Identification of a Family of Dual Receptor-Binding PfEMP1 that Is Associated with Cerebral Malaria","volume":"21","author":"Lennartz","year":"2017","journal-title":"Cell Host Microbe"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1016\/j.ijpara.2006.05.007","article-title":"Activation, silencing and mutually exclusive expression within the var gene family of Plasmodium falciparum","volume":"36","author":"Frank","year":"2006","journal-title":"Int. J. Parasitol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5418","DOI":"10.1093\/emboj\/17.18.5418","article-title":"Antigenic variation in malaria: In situ switching, relaxed and mutually exclusive transcription of var genes during intra-erythrocytic development in Plasmodium falciparum","volume":"17","author":"Scherf","year":"1998","journal-title":"EMBO J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.molbiopara.2006.03.004","article-title":"Disguising itself--insights into Plasmodium falciparum binding and immune evasion from the DBL crystal structure","volume":"148","author":"Howell","year":"2006","journal-title":"Mol. Biochem. Parasitol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1111\/j.1365-2958.2007.06019.x","article-title":"Mapping a common interaction site used by Plasmodium falciparum Duffy binding-like domains to bind diverse host receptors","volume":"67","author":"Howell","year":"2008","journal-title":"Mol. Microbiol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Oleinikov, A.V., Amos, E., Frye, I.T., Rossnagle, E., Mutabingwa, T.K., Fried, M., and Duffy, P.E. (2009). High throughput functional assays of the variant antigen PfEMP1 reveal a single domain in the 3D7 Plasmodium falciparum genome that binds ICAM1 with high affinity and is targeted by naturally acquired neutralizing antibodies. PLoS Pathog., 5.","DOI":"10.1371\/journal.ppat.1000386"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"240","DOI":"10.4049\/jimmunol.1202578","article-title":"A Novel Domain Cassette Identifies Plasmodium falciparum PfEMP1 Proteins Binding ICAM-1 and Is a Target of Cross-Reactive, Adhesion-Inhibitory Antibodies","volume":"190","author":"Bengtsson","year":"2013","journal-title":"J. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1799","DOI":"10.1056\/NEJMoa1303944","article-title":"Parasite burden and severity of malaria in Tanzanian children","volume":"370","author":"Goncalves","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_20","first-page":"1","article-title":"Clinical and parasitological studies on immunity to Plasmodium falciparum malaria in children","volume":"102","author":"Hogh","year":"1996","journal-title":"Scand. J. Infect. Dis. Suppl."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Rask, T.S., Hansen, D.A., Theander, T.G., Gorm Pedersen, A., and Lavstsen, T. (2010). Plasmodium falciparum erythrocyte membrane protein 1 diversity in seven genomes--divide and conquer. PLoS Comp. Biol., 6.","DOI":"10.1371\/journal.pcbi.1000933"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Gullingsrud, J., Saveria, T., Amos, E., Duffy, P.E., and Oleinikov, A.V. (2013). Structure-function-immunogenicity studies of PfEMP1 domain DBL2betaPF11_0521, a malaria parasite ligand for ICAM-1. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0061323"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Oleinikov, A.V., Voronkova, V.V., Frye, I.T., Amos, E., Morrison, R., Fried, M., and Duffy, P.E. (2012). A Plasma Survey Using 38 PfEMP1 Domains Reveals Frequent Recognition of the Plasmodium falciparum Antigen VAR2CSA among Young Tanzanian Children. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0031011"},{"key":"ref_24","unstructured":"Tessema, S.K., Utama, D., Chesnokov, O., Hodder, A.N., Lin, C.S., Harrison, G.L.A., Jespersen, J.S., Petersen, B., Tavul, L., and Siba, P. (2018). Antibodies to ICAM1-binding PfEMP1-DBLbeta are biomarkers of protective immunity to malaria in a cohort of young children from Papua New Guinea. Infect. Immun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1918","DOI":"10.1093\/infdis\/jix230","article-title":"Parasites Causing Cerebral Falciparum Malaria Bind Multiple Endothelial Receptors and Express EPCR and ICAM-1-Binding PfEMP1","volume":"215","author":"Moussiliou","year":"2017","journal-title":"J. Infect. Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1182\/blood-2013-03-490219","article-title":"Loss of endothelial protein C receptors links coagulation and inflammation to parasite sequestration in cerebral malaria in African children","volume":"122","author":"Moxon","year":"2013","journal-title":"Blood"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Avril, M., Bernabeu, M., Benjamin, M., Brazier, A.J., and Smith, J.D. (2016). Interaction between Endothelial Protein C Receptor and Intercellular Adhesion Molecule 1 to Mediate Binding of Plasmodium falciparum-Infected Erythrocytes to Endothelial Cells. MBio, 7.","DOI":"10.1128\/mBio.00615-16"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1073\/pnas.1712879115","article-title":"Infected erythrocytes expressing DC13 PfEMP1 differ from recombinant proteins in EPCR-binding function","volume":"115","author":"Azasi","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3633","DOI":"10.1161\/01.CIR.96.10.3633","article-title":"Human protein C receptor is present primarily on endothelium of large blood vessels: Implications for the control of the protein C pathway","volume":"96","author":"Laszik","year":"1997","journal-title":"Circulation"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/j.chom.2017.09.009","article-title":"Linking EPCR-Binding PfEMP1 to Brain Swelling in Pediatric Cerebral Malaria","volume":"22","author":"Kessler","year":"2017","journal-title":"Cell Host Microbe"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.1093\/infdis\/jiu589","article-title":"High throughput screening platform identifies small molecules that prevent sequestration of Plasmodium falciparum-infected erythrocytes","volume":"211","author":"Gullingsrud","year":"2015","journal-title":"J. Infect. Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1021\/cc7001205","article-title":"Strategies for the use of mixture-based synthetic combinatorial libraries: Scaffold ranking, direct testing in vivo, and enhanced deconvolution by computational methods","volume":"10","author":"Houghten","year":"2008","journal-title":"J. Comb. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Janes, J.H., Wang, C.P., Levin-Edens, E., Vigan-Womas, I., Guillotte, M., Melcher, M., Mercereau-Puijalon, O., and Smith, J.D. (2011). Investigating the host binding signature on the Plasmodium falciparum PfEMP1 protein family. PLoS Pathog., 7.","DOI":"10.1371\/journal.ppat.1002032"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"12837","DOI":"10.1038\/ncomms12837","article-title":"The structural basis for CD36 binding by the malaria parasite","volume":"7","author":"Hsieh","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1097\/01.moh.0000219655.73162.42","article-title":"Modulation of malaria virulence by determinants of Plasmodium falciparum erythrocyte membrane protein-1 display","volume":"13","author":"Fairhurst","year":"2006","journal-title":"Curr. Opin. Hematol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"29317","DOI":"10.1038\/srep29317","article-title":"Rosette-Disrupting Effect of an Anti-Plasmodial Compound for the Potential Treatment of Plasmodium falciparum Malaria Complications","volume":"6","author":"Moll","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"10103","DOI":"10.1021\/jm401543h","article-title":"Scaffold ranking and positional scanning utilized in the discovery of nAChR-selective compounds suitable for optimization studies","volume":"56","author":"Wu","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1021\/ci800426u","article-title":"Chemoinformatic analysis of combinatorial libraries, drugs, natural products, and molecular libraries small molecule repository","volume":"49","author":"Singh","year":"2009","journal-title":"J. Chem. Inf. Model."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5932","DOI":"10.1016\/j.bmc.2008.04.061","article-title":"Conformation-opioid activity relationships of bicyclic guanidines from 3D similarity analysis","volume":"16","author":"Giulianotti","year":"2008","journal-title":"Bioorg. Med. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1021\/ci800379q","article-title":"Characterization of activity landscapes using 2D and 3D similarity methods: Consensus activity cliffs","volume":"49","author":"Bender","year":"2009","journal-title":"J. Chem. Inf. Model."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2427","DOI":"10.1021\/ci200281v","article-title":"Multitarget structure-activity relationships characterized by activity-difference maps and consensus similarity measure","volume":"51","author":"Yongye","year":"2011","journal-title":"J. Chem. Inf. Model."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/s12936-016-1675-x","article-title":"New developments in anti-malarial target candidate and product profiles","volume":"16","author":"Burrows","year":"2017","journal-title":"Malar. J."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1038\/nature12216","article-title":"Severe malaria is associated with parasite binding to endothelial protein C receptor","volume":"498","author":"Turner","year":"2013","journal-title":"Nature"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Olsen, R.W., Ecklu-Mensah, G., Bengtsson, A., Ofori, M.F., Lusingu, J.P.A., Castberg, F.C., Hviid, L., Adams, Y., and Jensen, A.T.R. (2018). Natural and Vaccine-Induced Acquisition of Cross-Reactive IgG-Inhibiting ICAM-1-Specific Binding of a Plasmodium falciparum PfEMP1 Subtype Associated Specifically with Cerebral Malaria. Infect. Immun., 86.","DOI":"10.1128\/IAI.00622-17"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Bernabeu, M., Gunnarsson, C., Vishnyakova, M., Howard, C.C., Nagao, R.J., Avril, M., Taylor, T.E., Seydel, K.B., Zheng, Y., and Smith, J.D. (2019). Binding Heterogeneity of Plasmodium falciparum to Engineered 3D Brain Microvessels Is Mediated by EPCR and ICAM-1. MBio, 10.","DOI":"10.1128\/mBio.00420-19"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Storm, J., Jespersen, J.S., Seydel, K.B., Szestak, T., Mbewe, M., Chisala, N.V., Phula, P., Wang, C.W., Taylor, T.E., and Moxon, C.A. (2019). Cerebral malaria is associated with differential cytoadherence to brain endothelial cells. EMBO Mol. Med., 11.","DOI":"10.15252\/emmm.201809164"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/S0165-5728(02)00114-5","article-title":"The adhesion molecule ICAM-1 and its regulation in relation with the blood-brain barrier","volume":"128","author":"Dietrich","year":"2002","journal-title":"J. Neuroimmunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1623","DOI":"10.1007\/s00018-003-2347-x","article-title":"Tumor necrosis factor alpha in the pathogenesis of cerebral malaria","volume":"60","author":"Gimenez","year":"2003","journal-title":"Cell. Mol. Life Sci. CMLS"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"5131","DOI":"10.1073\/pnas.82.15.5131","article-title":"General method for the rapid solid-phase synthesis of large numbers of peptides: Specificity of antigen-antibody interaction at the level of individual amino acids","volume":"82","author":"Houghten","year":"1985","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1021\/cc000061t","article-title":"Solid-phase synthesis of bis-heterocyclic compounds from resin-bound orthogonally protected lysine","volume":"3","author":"Nefzi","year":"2001","journal-title":"J. Comb. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3349","DOI":"10.1021\/ol000225e","article-title":"Solid-phase synthesis of bis-2-imidazolidinethiones from resin-bound tripeptides","volume":"2","author":"Nefzi","year":"2000","journal-title":"Org. Lett."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"17871","DOI":"10.1038\/s41598-018-36071-2","article-title":"Plasmodium falciparum infected erythrocytes can bind to host receptors integrins alphaVbeta3 and alphaVbeta6 through DBLdelta1_D4 domain of PFL2665c PfEMP1 protein","volume":"8","author":"Chesnokov","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.molbiopara.2017.06.004","article-title":"Nicotinamide inhibits the growth of P. falciparum and enhances the antimalarial effect of artemisinin, chloroquine and pyrimethamine","volume":"216","author":"Tcherniuk","year":"2017","journal-title":"Mol. Biochem. Parasitol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1186\/s12936-015-0952-4","article-title":"Anti-malarial effect of semi-synthetic drug amitozyn","volume":"14","author":"Tcherniuk","year":"2015","journal-title":"Malar. J."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/11\/5659\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:08:13Z","timestamp":1760162893000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/11\/5659"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,26]]},"references-count":54,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["ijms22115659"],"URL":"https:\/\/doi.org\/10.3390\/ijms22115659","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,26]]}}}