{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T09:43:24Z","timestamp":1774345404105,"version":"3.50.1"},"reference-count":54,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2024,10,21]],"date-time":"2024-10-21T00:00:00Z","timestamp":1729468800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000057","name":"HHS | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35GM140852"],"award-info":[{"award-number":["R35GM140852"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Aptamers are short, single-stranded oligonucleotides that selectively bind to target biomolecules. Although they generally exhibit good binding specificity, their affinities are often limited because of the relative lack of hydrophobic groups in nucleic acids. Chemically modified nucleotides incorporating hydrophobic structures into uracil have been synthesized to address this obstacle. Modified DNA aptamers containing such nonstandard nucleotides have been developed for &amp;gt;20 different complement proteins. These modified aptamers show increased affinity and enhanced serum stability and have potential value as therapeutic agents. We recently conducted a structure\/function study on a family of modified DNA aptamers that bind specifically to complement Factor B (FB). This work revealed that these aptamers selectively inhibit the complement alternative pathway (AP) by preventing the formation of the AP complement component C3 (C3) proconvertase complex, C3bB. Certain patients with atypical hemolytic uremic syndrome express gain-of-function variants of FB that enhance the formation of the proconvertase complex and\/or decrease the efficacy of endogenous regulators against the C3 convertases they form. To investigate whether these FB-binding aptamers could override the effects of disease-causing mutations in FB, we examined how they interacted with several FB variants, including D279G, F286L, K323E, and K350N, in various assays of complement function. We found that the inhibitory effect of the FB-binding aptamers superseded the gain-of-function mutations in FB, although the aptamers could not dissociate preformed C3 convertases. These findings suggest that FB-binding aptamers could be further developed as a potential treatment for certain atypical hemolytic uremic syndrome patients or those with other diseases characterized by excessive complement activity.<\/jats:p>","DOI":"10.4049\/jimmunol.2400420","type":"journal-article","created":{"date-parts":[[2024,10,21]],"date-time":"2024-10-21T13:25:19Z","timestamp":1729517119000},"page":"1691-1702","source":"Crossref","is-referenced-by-count":1,"title":["The Inhibitory Effects of a Factor B\u2013Binding DNA Aptamer Family Supersede the Gain of Function of Factor B Variants Associated with Atypical Hemolytic Uremic Syndrome"],"prefix":"10.1093","volume":"213","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3351-8618","authenticated-orcid":false,"given":"Huiquan","family":"Duan","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biophysics, Kansas State University , Manhattan, KS"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1603-7561","authenticated-orcid":false,"given":"Ying","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biophysics, Kansas State University , Manhattan, KS"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew R","family":"Otis","sequence":"additional","affiliation":[{"name":"SomaLogic , Boulder, CO"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel W","family":"Drolet","sequence":"additional","affiliation":[{"name":"SomaLogic , Boulder, CO"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1775-0727","authenticated-orcid":false,"given":"Brian V","family":"Geisbrecht","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biophysics, Kansas State University , Manhattan, KS"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2024,10,21]]},"reference":[{"key":"2025020609300733400_r1","doi-asserted-by":"crossref","first-page":"262","DOI":"10.3389\/fimmu.2015.00262","article-title":"Complement system part I\u2014molecular mechanisms of activation and regulation","volume":"6","author":"Merle","year":"2015","journal-title":"Front. Immunol."},{"key":"2025020609300733400_r2","doi-asserted-by":"crossref","first-page":"257","DOI":"10.3389\/fimmu.2015.00257","article-title":"Complement system part II: role in immunity","volume":"6","author":"Merle","year":"2015","journal-title":"Front. Immunol."},{"key":"2025020609300733400_r3","doi-asserted-by":"crossref","first-page":"101627","DOI":"10.1016\/j.smim.2022.101627","article-title":"Complement component C3: a structural perspective and potential therapeutic implications","volume":"59","author":"Geisbrecht","year":"2022","journal-title":"Semin. Immunol."},{"key":"2025020609300733400_r4","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1042\/bj2350723","article-title":"The C3 convertase of the alternative pathway of human complement. Enzymic properties of the biomolecular proteinase","volume":"235","author":"Pangburn","year":"1986","journal-title":"Biochem. J."},{"key":"2025020609300733400_r5","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.molimm.2018.05.018","article-title":"Properdin: a multifaceted molecule involved in inflammation and diseases","volume":"102","author":"Chen","year":"2018","journal-title":"Mol. Immunol."},{"key":"2025020609300733400_r6","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1084\/jem.135.4.1003","article-title":"C3 proactivator convertase and its mode of action","volume":"135","author":"Muller-Eberhard","year":"1972","journal-title":"J. Exp. Med"},{"key":"2025020609300733400_r7","doi-asserted-by":"crossref","first-page":"1930","DOI":"10.4049\/jimmunol.131.4.1930","article-title":"C3b deposition during activation of the alternative complement pathway and the effect of deposition on the activating surface","volume":"131","author":"Pangburn","year":"1983","journal-title":"J. Immunol"},{"key":"2025020609300733400_r8","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1111\/j.1365-2249.2004.02627.x","article-title":"The quantitative role of alternative pathway amplification in classical pathway induced terminal complement activation","volume":"138","author":"Harboe","year":"2004","journal-title":"Clin. Exp. Immunol."},{"key":"2025020609300733400_r9","doi-asserted-by":"crossref","first-page":"530","DOI":"10.3389\/fimmu.2020.00530","article-title":"Assessment of the role of C3(H2O) in the alternative pathway","volume":"11","author":"Fromell","year":"2020","journal-title":"Front. Immunol."},{"key":"2025020609300733400_r10","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1038\/nri2620","article-title":"Complement regulators and inhibitory proteins","volume":"9","author":"Zipfel","year":"2009","journal-title":"Nat. Rev. Immunol."},{"key":"2025020609300733400_r11","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1007\/s00281-017-0663-8","article-title":"Diseases of complement dysregulation\u2014an overview","volume":"40","author":"Wong","year":"2018","journal-title":"Semin. Immunopathol."},{"key":"2025020609300733400_r12","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1093\/ckj\/sfy066","article-title":"Atypical hemolytic uremic syndrome: a syndrome in need of clarity","volume":"12","author":"Berger","year":"2018","journal-title":"Clin. Kidney J."},{"key":"2025020609300733400_r13","doi-asserted-by":"crossref","first-page":"99","DOI":"10.5551\/jat.RV17026","article-title":"Pathogenesis of atypical hemolytic uremic syndrome","volume":"26","author":"Yoshida","year":"2019","journal-title":"J. Atheroscler. Thromb."},{"key":"2025020609300733400_r14","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1055\/s-0034-1375296","article-title":"Genetics of atypical hemolytic uremic syndrome (aHUS)","volume":"40","author":"Rodr\u00edguez de C\u00f3rdoba","year":"2014","journal-title":"Semin. Thromb. Hemost."},{"key":"2025020609300733400_r15","doi-asserted-by":"crossref","first-page":"c219","DOI":"10.1159\/000276545","article-title":"Atypical hemolytic uremic syndrome: update on the complement system and what is new","volume":"114","author":"Hirt-Minkowski","year":"2010","journal-title":"Nephron. Clin. Pract."},{"key":"2025020609300733400_r16","doi-asserted-by":"crossref","first-page":"2431","DOI":"10.1007\/s00467-010-1555-5","article-title":"Genetics and complement in atypical HUS","volume":"25","author":"Kavanagh","year":"2010","journal-title":"Pediatr. Nephrol."},{"key":"2025020609300733400_r17","doi-asserted-by":"crossref","first-page":"1676","DOI":"10.1056\/NEJMra0902814","article-title":"Atypical hemolytic-uremic syndrome","volume":"361","author":"Noris","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"2025020609300733400_r18","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1086\/344515","article-title":"Structural and functional characterization of factor H mutations associated with atypical hemolytic uremic syndrome","volume":"71","author":"S\u00e1nchez-Corral","year":"2002","journal-title":"Am. J. Hum. Genet."},{"key":"2025020609300733400_r19","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1172\/JCI16651","article-title":"Mutations in factor H reduce binding affinity to C3b and heparin and surface attachment to endothelial cells in hemolytic uremic syndrome","volume":"111","author":"Manuelian","year":"2003","journal-title":"J. Clin. Invest."},{"key":"2025020609300733400_r20","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.molimm.2004.01.003","article-title":"Functional analysis in serum from atypical hemolytic uremic syndrome patients reveals impaired protection of host cells associated with mutations in factor H","volume":"41","author":"Sanchez-Corral","year":"2004","journal-title":"Mol. Immunol"},{"key":"2025020609300733400_r21","doi-asserted-by":"crossref","first-page":"12966","DOI":"10.1073\/pnas.2135497100","article-title":"Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome","volume":"100","author":"Richards","year":"2003","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2025020609300733400_r22","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.molimm.2007.05.004","article-title":"Characterization of mutations in complement factor I (CFI) associated with hemolytic uremic syndrome","volume":"45","author":"Kavanagh","year":"2008","journal-title":"Mol. Immunol."},{"key":"2025020609300733400_r23","doi-asserted-by":"crossref","first-page":"4948","DOI":"10.1182\/blood-2008-01-133702","article-title":"Mutations in complement C3 predispose to development of atypical hemolytic uremic syndrome","volume":"112","author":"Fr\u00e9meaux-Bacchi","year":"2008","journal-title":"Blood"},{"key":"2025020609300733400_r24","doi-asserted-by":"crossref","first-page":"2053","DOI":"10.1681\/ASN.2013070796","article-title":"Complement factor B mutations in atypical hemolytic uremic syndrome\u2014disease-relevant or benign?","volume":"25","author":"Marinozzi","year":"2014","journal-title":"J. Am. Soc. Nephrol."},{"key":"2025020609300733400_r25","doi-asserted-by":"crossref","first-page":"2837","DOI":"10.1182\/blood-2009-01-197640","article-title":"Hyperfunctional C3 convertase leads to complement deposition on endothelial cells and contributes to atypical hemolytic uremic syndrome","volume":"114","author":"Roumenina","year":"2009","journal-title":"Blood"},{"key":"2025020609300733400_r26","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1073\/pnas.0603420103","article-title":"Gain-of-function mutations in complement factor B are associated with atypical hemolytic uremic syndrome","volume":"104","author":"Goicoechea de Jorge","year":"2007","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2025020609300733400_r27","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.bbadis.2010.09.002","article-title":"Lessons from functional and structural analyses of disease-associated genetic variants in the complement alternative pathway","volume":"1812","author":"Rodr\u00edguez de C\u00f3rdoba","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"2025020609300733400_r28","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1007\/s00467-010-1556-4","article-title":"aHUS caused by complement dysregulation: new therapies on the horizon","volume":"26","author":"Waters","year":"2011","journal-title":"Pediatr. Nephrol."},{"key":"2025020609300733400_r29","doi-asserted-by":"crossref","first-page":"3253","DOI":"10.1182\/blood-2014-09-600411","article-title":"Eculizumab reduces complement activation, inflammation, endothelial damage, thrombosis, and renal injury markers in aHUS","volume":"125","author":"Cofiell","year":"2015","journal-title":"Blood"},{"key":"2025020609300733400_r30","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.molimm.2013.05.224","article-title":"Complement therapy in atypical haemolytic uraemic syndrome (aHUS)","volume":"56","author":"Wong","year":"2013","journal-title":"Mol. Immunol."},{"key":"2025020609300733400_r31","doi-asserted-by":"crossref","first-page":"2169","DOI":"10.1056\/NEJMoa1208981","article-title":"Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome","volume":"368","author":"Legendre","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"2025020609300733400_r32","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1007\/s00467-013-2492-x","article-title":"Eculizumab therapy for atypical haemolytic uraemic syndrome due to a gain-of-function mutation of complement factor B","volume":"28","author":"Gilbert","year":"2013","journal-title":"Pediatr. Nephrol."},{"key":"2025020609300733400_r33","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1016\/j.ekir.2023.04.029","article-title":"Design and rationale of the APPELHUS phase 3 open-label study of factor B inhibitor iptacopan for atypical hemolytic uremic syndrome","volume":"8","author":"Kavanagh","year":"2023","journal-title":"Kidney Int. Rep."},{"key":"2025020609300733400_r34","doi-asserted-by":"crossref","first-page":"861","DOI":"10.4049\/jimmunol.2001260","article-title":"Inhibition of the complement alternative pathway by chemically modified DNA aptamers that bind with picomolar affinity to factor B","volume":"206","author":"Xu","year":"2021","journal-title":"J. Immunol"},{"key":"2025020609300733400_r35","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1038\/nrd4657","article-title":"Complement, a target for therapy in inflammatory and degenerative diseases","volume":"14","author":"Morgan","year":"2015","journal-title":"Nat. Rev. Drug Discov."},{"key":"2025020609300733400_r36","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/B978-0-12-418687-3.00018-5","article-title":"Transient mammalian cell transfection with polyethylenimine (PEI)","volume":"529","author":"Longo","year":"2013","journal-title":"Methods Enzymol."},{"key":"2025020609300733400_r37","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/0076-6879(87)54081-2","article-title":"Chemical synthesis of deoxyoligonucleotides by the phosphoramidite method","volume":"154","author":"Caruthers","year":"1987","journal-title":"Methods Enzymol."},{"key":"2025020609300733400_r38","doi-asserted-by":"crossref","first-page":"4141","DOI":"10.1021\/ja908035g","article-title":"Expanding the chemistry of DNA for in vitro selection","volume":"132","author":"Vaught","year":"2010","journal-title":"J. Am. Chem. Soc."},{"key":"2025020609300733400_r39","doi-asserted-by":"crossref","first-page":"e201","DOI":"10.1038\/mtna.2014.49","article-title":"Nucleic acid ligands with protein-like side chains: modified aptamers and their use as diagnostic and therapeutic agents","volume":"3","author":"Rohloff","year":"2014","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"2025020609300733400_r40","doi-asserted-by":"crossref","first-page":"3705","DOI":"10.4049\/jimmunol.1601932","article-title":"Identification of C3b-binding small-molecule complement inhibitors using cheminformatics","volume":"198","author":"Garcia","year":"2017","journal-title":"J. Immunol."},{"key":"2025020609300733400_r41","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.4049\/jimmunol.2101078","article-title":"Group B streptococcus surface protein \u03b2: structural characterization of a complement factor H-binding motif and its contribution to immune evasion","volume":"208","author":"Xu","year":"2022","journal-title":"J. Immunol."},{"key":"2025020609300733400_r42","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1038\/nsmb1210","article-title":"Factor B structure provides insights into activation of the central protease of the complement system","volume":"14","author":"Milder","year":"2007","journal-title":"Nat. Struct. Mol. Biol."},{"key":"2025020609300733400_r43","doi-asserted-by":"crossref","first-page":"2906","DOI":"10.4049\/jimmunol.162.5.2906","article-title":"Mutations of the type A domain of complement factor B that promote high-affinity C3b-binding","volume":"162","author":"Hourcade","year":"1999","journal-title":"J. Immunol."},{"key":"2025020609300733400_r44","doi-asserted-by":"crossref","first-page":"17621","DOI":"10.1073\/pnas.1003750107","article-title":"Allosteric inhibition of complement function by a Staphylococcal immune evasion protein","volume":"107","author":"Chen","year":"2010","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2025020609300733400_r45","doi-asserted-by":"crossref","first-page":"1816","DOI":"10.1126\/science.1195821","article-title":"Structures of C3b in complex with factors B and D give insight into complement convertase formation","volume":"330","author":"Forneris","year":"2010","journal-title":"Science"},{"key":"2025020609300733400_r46","doi-asserted-by":"crossref","first-page":"2730","DOI":"10.1074\/mcp.M115.056473","article-title":"Structure of complement C3(H2O) revealed by quantitative cross-linking\/mass spectrometry and modeling","volume":"15","author":"Chen","year":"2016","journal-title":"Mol. Cell. Proteomics"},{"key":"2025020609300733400_r47","doi-asserted-by":"crossref","first-page":"4458","DOI":"10.1021\/bi00518a034","article-title":"Nucleophilic modification of human complement protein C3: correlation of conformational changes with acquisition of C3b-like functional properties","volume":"20","author":"Isenman","year":"1981","journal-title":"Biochemistry"},{"key":"2025020609300733400_r48","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1084\/jem.154.3.856","article-title":"Formation of the initial C3 convertase of the alternative pathway: acquisition of C3b-like activities by spontaneous hydrolysis of the putative thioester in native C3","volume":"154","author":"Pangburn","year":"1981","journal-title":"J. Exp. Med."},{"key":"2025020609300733400_r49","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1038\/nrd3141","article-title":"Aptamers as therapeutics","volume":"9","author":"Keefe","year":"2010","journal-title":"Nat. Rev. Drug. Discov."},{"key":"2025020609300733400_r50","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1146\/annurev-pharmtox-010716-104558","article-title":"Aptamers as therapeutics","volume":"57","author":"Nimjee","year":"2017","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"2025020609300733400_r51","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1007\/s40265-023-01948-8","article-title":"Avacincaptad Pegol: first approval","volume":"83","author":"Kang","year":"2023","journal-title":"Drugs"},{"key":"2025020609300733400_r52","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/S0162-3109(99)00020-X","article-title":"Derivation of RNA aptamer inhibitors of human complement C5","volume":"42","author":"Biesecker","year":"1999","journal-title":"Immunopharmacology"},{"key":"2025020609300733400_r53","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/nrd.2016.199","article-title":"Aptamers as targeted therapeutics: current potential and challenges","volume":"16","author":"Zhou","year":"2017","journal-title":"Nat. Rev. Drug Discov."},{"key":"2025020609300733400_r54","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.addr.2018.10.008","article-title":"Pharmacokinetics, pharmacodynamics and safety of aptamers","volume":"134","author":"Kovacevic","year":"2018","journal-title":"Adv. Drug Deliv. Rev."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/213\/11\/1691\/61497197\/ji2400420.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/213\/11\/1691\/61497197\/ji2400420.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,6]],"date-time":"2025-02-06T09:32:21Z","timestamp":1738834341000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/213\/11\/1691\/7960676"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,21]]},"references-count":54,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2024,12,1]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.2400420","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,12]]},"published":{"date-parts":[[2024,10,21]]}}}