{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,6]],"date-time":"2025-12-06T17:19:48Z","timestamp":1765041588920,"version":"build-2065373602"},"reference-count":57,"publisher":"MDPI AG","issue":"10","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:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Sciences Foundation of China","award":["81973321","82204602","2022CFB956","2023AFB296","2021QDJZR019","2021QDJZR022"],"award-info":[{"award-number":["81973321","82204602","2022CFB956","2023AFB296","2021QDJZR019","2021QDJZR022"]}]},{"name":"Natural Science Foundation of Hubei Provincial Department of Science and Technology","award":["81973321","82204602","2022CFB956","2023AFB296","2021QDJZR019","2021QDJZR022"],"award-info":[{"award-number":["81973321","82204602","2022CFB956","2023AFB296","2021QDJZR019","2021QDJZR022"]}]},{"name":"School Natural Science Fund of the Hubei University of Medicine","award":["81973321","82204602","2022CFB956","2023AFB296","2021QDJZR019","2021QDJZR022"],"award-info":[{"award-number":["81973321","82204602","2022CFB956","2023AFB296","2021QDJZR019","2021QDJZR022"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Recent studies have revealed that the coagulation system plays a role in mammalian innate defense by entrapping bacteria in clots and generating antibacterial peptides. So, it is very important for the survival of bacteria to defend against the host coagulation system, which suggests that bacterial exotoxins might be a new source of anticoagulants. In this study, we analyzed the genomic sequences of Acinetobacter baumannii and a new bacterial exotoxin protein, F6W77, with five Kunitz-domains, KABP1-5, was identified. Each Kunitz-type domain features a classical six-cysteine framework reticulated by three conserved disulfide bridges, which was obviously similar to animal Kunitz-domain peptides but different from plant Kunitz-domain peptides. Anticoagulation function evaluation showed that towards the intrinsic coagulation pathway, KABP1 and KABP5 had apparently inhibitory activity, KABP4 had weak inhibitory activity, and KBAP2 and KABP3 had no effect even at a high concentration of 20 \u03bcg\/mL. All five Kunitz-domain peptides, KABP1-5, had no inhibitory activity towards the extrinsic coagulation pathway. Enzyme-inhibitor experiments showed that the high-activity anticoagulant peptide KABP1 had apparently inhibitory activity towards two key coagulation factors, Xa and XIa, which was further confirmed by pull-down experiments that showed that KABP1 can bind to coagulation factors Xa and XIa directly. Structure-function relationship analyses of five Kunitz-type domain peptides showed that the arginine of the P1 site of three new bacterial anticoagulants, KABP1, KABP4 and KABP5, might be the key residue for their anticoagulation activity. In conclusion, with bioinformatics analyses, peptide recombination, and functional evaluation, we firstly found bacterial-exotoxin-derived Kunitz-type serine protease inhibitors with selectively inhibiting activity towards intrinsic coagulation pathways, and highlighted a new interaction between pathogenic bacteria and the human coagulation system.<\/jats:p>","DOI":"10.3390\/toxins16100450","type":"journal-article","created":{"date-parts":[[2024,10,21]],"date-time":"2024-10-21T09:58:24Z","timestamp":1729504704000},"page":"450","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Characterization of Kunitz-Domain Anticoagulation Peptides Derived from Acinetobacter baumannii Exotoxin Protein F6W77"],"prefix":"10.3390","volume":"16","author":[{"given":"Fang","family":"Sun","sequence":"first","affiliation":[{"name":"Institute of Biomedicine, Hubei Key Laboratory of Embryonic Stem Cell Research, and Hubei Key Laboratory of Wudang Local Chinese Medicine Research, College of Basic Medicine, Hubei University of Medicine, Shiyan 442000, China"},{"name":"Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan 442000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaolin","family":"Deng","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine, Hubei Key Laboratory of Embryonic Stem Cell Research, and Hubei Key Laboratory of Wudang Local Chinese Medicine Research, College of Basic Medicine, Hubei University of Medicine, Shiyan 442000, China"},{"name":"Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan 442000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huanhuan","family":"Gao","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine, Hubei Key Laboratory of Embryonic Stem Cell Research, and Hubei Key Laboratory of Wudang Local Chinese Medicine Research, College of Basic Medicine, Hubei University of Medicine, Shiyan 442000, China"},{"name":"Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan 442000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Ding","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine, Hubei Key Laboratory of Embryonic Stem Cell Research, and Hubei Key Laboratory of Wudang Local Chinese Medicine Research, College of Basic Medicine, Hubei University of Medicine, Shiyan 442000, China"},{"name":"Department of Clinical Laboratory, Dongfeng Hospital, Hubei University of Medicine, Shiyan 442000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen","family":"Zhu","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine, Hubei Key Laboratory of Embryonic Stem Cell Research, and Hubei Key Laboratory of Wudang Local Chinese Medicine Research, College of Basic Medicine, Hubei University of Medicine, Shiyan 442000, China"},{"name":"Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan 442000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongyi","family":"Luo","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine, Hubei Key Laboratory of Embryonic Stem Cell Research, and Hubei Key Laboratory of Wudang Local Chinese Medicine Research, College of Basic Medicine, Hubei University of Medicine, Shiyan 442000, China"},{"name":"Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan 442000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiangdong","family":"Ye","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine, Hubei Key Laboratory of Embryonic Stem Cell Research, and Hubei Key Laboratory of Wudang Local Chinese Medicine Research, College of Basic Medicine, Hubei University of Medicine, Shiyan 442000, China"},{"name":"Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan 442000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xudong","family":"Luo","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine, Hubei Key Laboratory of Embryonic Stem Cell Research, and Hubei Key Laboratory of Wudang Local Chinese Medicine Research, College of Basic Medicine, Hubei University of Medicine, Shiyan 442000, China"},{"name":"Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan 442000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9939-186X","authenticated-orcid":false,"given":"Zongyun","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine, Hubei Key Laboratory of Embryonic Stem Cell Research, and Hubei Key Laboratory of Wudang Local Chinese Medicine Research, College of Basic Medicine, Hubei University of Medicine, Shiyan 442000, China"},{"name":"Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan 442000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chenhu","family":"Qin","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine, Hubei Key Laboratory of Embryonic Stem Cell Research, and Hubei Key Laboratory of Wudang Local Chinese Medicine Research, College of Basic Medicine, Hubei University of Medicine, Shiyan 442000, China"},{"name":"Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan 442000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.blre.2014.09.003","article-title":"Fibrinolysis and the control of blood coagulation","volume":"29","author":"Chapin","year":"2015","journal-title":"Blood Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1038\/s41422-019-0202-3","article-title":"Coagulation factors VII, IX and X are effective antibacterial proteins against drug-resistant Gram-negative bacteria","volume":"29","author":"Chen","year":"2019","journal-title":"Cell Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1128\/IAI.00031-19","article-title":"A Phenome-Wide Association Study Uncovers a Pathological Role of Coagulation Factor X during Infection","volume":"87","author":"Choby","year":"2019","journal-title":"Infect. Immun."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1111\/1574-6976.12080","article-title":"Bacteria under stress by complement and coagulation","volume":"38","author":"Berends","year":"2014","journal-title":"Fems Microbiol. Rev."},{"key":"ref_5","unstructured":"(2021). Dahlman A, Puthia M, Petrlova J, Schmidtchen A, Petruk G. Thrombin-Derived C-Terminal Peptide Reduces Candida-Induced Inflammation and Infection In Vitro and In Vivo. Antimicrob. Agents Chemother., 65, 10-1128."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3260","DOI":"10.1182\/blood-2015-11-683110","article-title":"Matriptase activation connects tissue factor-dependent coagulation initiation to epithelial proteolysis and signaling","volume":"127","author":"Szabo","year":"2016","journal-title":"Blood"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1111\/jth.13653","article-title":"Clumping factor A, von Willebrand factor-binding protein and von Willebrand factor anchor to the vessel wall","volume":"15","author":"Claes","year":"2017","journal-title":"J. Thromb. Haemost."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1128\/IAI.00027-18","article-title":"Identification, Cloning, and Characterization of Staphylococcus pseudintermedius Coagulase","volume":"86","author":"Sewid","year":"2018","journal-title":"Infect. Immun."},{"key":"ref_9","first-page":"108","article-title":"Extracellular fibrinogen-binding protein (Efb) from inhibits fibrinogen binding, platelet aggregation and whole blood thrombus formation","volume":"11","author":"Shannon","year":"2013","journal-title":"J. Thromb. Haemost."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"12842","DOI":"10.1074\/jbc.M113.543546","article-title":"Evidence for Steric Regulation of Fibrinogen Binding to Staphylococcus aureus Fibronectin-binding Protein A (FnBPA)","volume":"289","author":"Stemberk","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"21569","DOI":"10.1074\/jbc.M113.451419","article-title":"Staphylococcal Superantigen-like Protein 10 (SSL10) Inhibits Blood Coagulation by Binding to Prothrombin and Factor Xa via Their \u03b3-Carboxyglutamic Acid (Gla) Domain","volume":"288","author":"Itoh","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1160\/TH11-03-0204","article-title":"Binding characteristics of thrombin-activatable fibrinolysis inhibitor to streptococcal surface collagen-like proteins A and B","volume":"106","author":"Plug","year":"2011","journal-title":"Thromb. Haemost."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"E13","DOI":"10.2500\/ajra.2017.31.4400","article-title":"Thrombin and activated coagulation factor X stimulate the release of cytokines and fibronectin from nasal polyp fibroblasts protease-activated receptors","volume":"31","author":"Shimizu","year":"2017","journal-title":"Am. J. Rhinol. Allergy"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1156","DOI":"10.1182\/bloodadvances.2021006485","article-title":"Anti-HK antibody inhibits the plasma contact system by blocking prekallikrein and factor XI activation in vivo","volume":"7","author":"Chen","year":"2023","journal-title":"Blood Adv."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1111\/1574-6968.12496","article-title":"CpaA a novel protease from clinical isolates deregulates blood coagulation","volume":"356","author":"Tilley","year":"2014","journal-title":"Fems Microbiol. Lett."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1128\/mBio.01606-18","article-title":"CpaA Is a Glycan-Specific Adamalysin-like Protease Secreted by Acinetobacter baumannii That Inactivates Coagulation Factor XII","volume":"9","author":"Waack","year":"2018","journal-title":"Mbio"},{"key":"ref_17","first-page":"577","article-title":"EspP, an extracellular serine protease from enterohemorrhagic, induces coagulopathy in human plasma and fibrinolysis in whole blood","volume":"9","author":"Kuo","year":"2011","journal-title":"J. Thromb. Haemost."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Monastyrnaya, M., Peigneur, S., Zelepuga, E., Sintsova, O., Gladkikh, I., Leychenko, E., Isaeva, M., Tytgat, J., and Kozlovskaya, E. (2016). Kunitz-Type Peptide HCRG21 from the Sea Anemone Heteractis crispa Is a Full Antagonist of the TRPV1 Receptor. Mar. Drugs, 14.","DOI":"10.3390\/md14120229"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"13813","DOI":"10.1074\/jbc.M112.343996","article-title":"Hg1, novel peptide inhibitor specific for Kv1.3 channels from first scorpion Kunitz-type potassium channel toxin family","volume":"287","author":"Chen","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.toxicon.2018.07.014","article-title":"The Kv1.3 channel-inhibitory toxin BF9 also displays anticoagulant activity via inhibition of factor XIa","volume":"152","author":"Ding","year":"2018","journal-title":"Toxicon."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1038\/s41590-023-01605-y","article-title":"Kunitz-type protease inhibitor TFPI2 remodels stemness and immunosuppressive tumor microenvironment in glioblastoma","volume":"24","author":"Pang","year":"2023","journal-title":"Nat Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1663","DOI":"10.1017\/S0031182015001328","article-title":"A novel coagulation inhibitor from Schistosoma japonicum","volume":"142","author":"Ranasinghe","year":"2015","journal-title":"Parasitology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1093\/hmg\/ddae005","article-title":"SPINT2 mutations in the Kunitz domain 2 found in SCSD patients inactivate HAI-2 as prostasin inhibitor via abnormal protein folding and N-glycosylation","volume":"33","author":"Huang","year":"2024","journal-title":"Hum Mol Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4094","DOI":"10.1182\/blood-2013-08-517474","article-title":"Desmolaris, a novel factor XIa anticoagulant from the salivary gland of the vampire bat (Desmodus rotundus) inhibits inflammation and thrombosis in vivo","volume":"122","author":"Ma","year":"2013","journal-title":"Blood"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1182\/blood-2012-03-419523","article-title":"The kunitz protease inhibitor domain of protease nexin-2 inhibits factor XIa and murine carotid artery and middle cerebral artery thrombosis","volume":"120","author":"Wu","year":"2012","journal-title":"Blood"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3602","DOI":"10.1182\/blood-2001-12-0237","article-title":"Ixolaris, a novel recombinant tissue factor pathway inhibitor (TFPI) from the salivary gland of the tick, Ixodes scapularis: Identification of factor X and factor Xa as scaffolds for the inhibition of factor VIIa\/tissue factor complex","volume":"99","author":"Francischetti","year":"2002","journal-title":"Blood"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1428","DOI":"10.1016\/j.bbapap.2016.07.011","article-title":"Amblyomin-X having a Kunitz-type homologous domain, is a noncompetitive inhibitor of FXa and induces anticoagulation in vitro and in vivo","volume":"1864","author":"Branco","year":"2016","journal-title":"Biochim. Et Biophys. Acta-Proteins Proteom."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Fl\u00f3, M., Margenat, M., Pellizza, L., Gra\u00f1a, M., Dur\u00e1n, R., B\u00e1ez, A., Salceda, E., Soto, E., Alvarez, B., and Fern\u00e1ndez, C. (2017). Functional diversity of secreted cestode Kunitz proteins: Inhibition of serine peptidases and blockade of cation channels. PLoS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006169"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1002\/jbt.21538","article-title":"BF9, the first functionally characterized snake toxin peptide with Kunitz-type protease and potassium channel inhibiting properties","volume":"28","author":"Yang","year":"2014","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1006\/jmbi.1993.1210","article-title":"Crystal structures of rat anionic trypsin complexed with the protein inhibitors APPI and BPTI","volume":"230","author":"Perona","year":"1993","journal-title":"J. Mol. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2089","DOI":"10.1006\/jmbi.1998.2452","article-title":"Structure of extracellular tissue factor complexed with factor VIIa inhibited with a BPTI mutant","volume":"285","author":"Zhang","year":"1999","journal-title":"J. Mol. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1093\/jb\/mvs133","article-title":"P1 and P2\u2019 site mutations convert protease nexin-2 from a factor XIa inhibitor to a plasmin inhibitor","volume":"153","author":"Navaneetham","year":"2013","journal-title":"J. Biochem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1182\/blood.2019000919","article-title":"Novel antithrombotic strategies for treatment of venous thromboembolism","volume":"135","author":"Weitz","year":"2020","journal-title":"Blood"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1161\/ATVBAHA.119.313503","article-title":"Plasma Kallikrein Contributes to Coagulation in the Absence of Factor XI by Activating Factor IX","volume":"40","author":"Visser","year":"2020","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1111\/jth.13760","article-title":"A kallikrein-targeting RNA aptamer inhibits the intrinsic pathway of coagulation and reduces bradykinin release","volume":"15","author":"Layzer","year":"2017","journal-title":"J. Thromb. Haemost."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.1111\/jth.12302","article-title":"Inhibiting the intrinsic pathway of coagulation with a factor XII-targeting RNA aptamer","volume":"11","author":"Woodruff","year":"2013","journal-title":"J. Thromb. Haemost."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1016\/j.hoc.2016.05.007","article-title":"The Intrinsic Pathway of Coagulation as a Target for Antithrombotic Therapy","volume":"30","author":"Wheeler","year":"2016","journal-title":"Hematol. Oncol. Clin. North Am."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"32","DOI":"10.2174\/187152810791292890","article-title":"Blood coagulation as an intrinsic pathway for proinflammation: A mini review","volume":"9","author":"Chu","year":"2010","journal-title":"Inflamm Allergy Drug Targets"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4684","DOI":"10.1182\/blood-2010-04-277798","article-title":"Inhibition of the intrinsic coagulation pathway factor XI by antisense oligonucleotides: A novel antithrombotic strategy with lowered bleeding risk","volume":"116","author":"Zhang","year":"2010","journal-title":"Blood"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.biochi.2016.08.005","article-title":"Structural and functional characterization of complex formation between two Kunitz-type serine protease inhibitors from Russell\u2019s Viper venom","volume":"128","author":"Mukherjee","year":"2016","journal-title":"Biochimie"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1016\/j.ijbiomac.2018.08.178","article-title":"Engineering varied serine protease inhibitors by converting P1 site of BF9, a weakly active Kunitz-type animal toxin","volume":"120 Pt A","author":"Ding","year":"2018","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1111\/jth.12797","article-title":"Fasxiator, a novel factor XIa inhibitor from snake venom, and its site-specific mutagenesis to improve potency and selectivity","volume":"13","author":"Chen","year":"2015","journal-title":"J. Thromb. Haemost."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Tsujimoto, H., Kotsyfakis, M., Francischetti, I.M.B., Eum, J.H., Strand, M.R., and Champagne, D.E. (2012). Simukunin from the salivary glands of the black fly Simulium vittatum inhibits enzymes that regulate clotting and inflammatory responses. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0029964"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1160\/TH16-11-0829","article-title":"Joannsin, a novel Kunitz-type FXa inhibitor from the venom of Prospirobolus joannsi","volume":"117","author":"Luan","year":"2017","journal-title":"Thromb. Haemost."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1096\/fj.11-190207","article-title":"Structural features of the KPI domain control APP dimerization, trafficking, and processing","volume":"26","author":"Tyteca","year":"2012","journal-title":"Faseb J."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1126\/science.2333510","article-title":"Tick anticoagulant peptide (TAP) is a novel inhibitor of blood coagulation factor Xa","volume":"248","author":"Waxman","year":"1990","journal-title":"Science"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.cbpb.2009.02.010","article-title":"A novel serine protease inhibitor from the venom of Fabricius","volume":"153","author":"Yang","year":"2009","journal-title":"Comp. Biochem. Physiol. B-Biochem. Mol. Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.ijpara.2018.11.010","article-title":"A novel Kunitz protein with proposed dual function from Eudiplozoon nipponicum (Monogenea) impairs haemostasis and action of complement in vitro","volume":"49","year":"2019","journal-title":"Int. J. Parasitol."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Morais, S.B., Figueiredo, B.C., Assis, N.R.G., Alvarenga, D.M., de Magalh\u00e3es, M.T.Q., Ferreira, R.S., Vieira, A.T., Menezes, G.B., and Oliveira, S.C. (2018). Schistosoma mansoni SmKI-1 serine protease inhibitor binds to elastase and impairs neutrophil function and inflammation. PLoS Pathog., 14.","DOI":"10.1371\/journal.ppat.1006870"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.bbrc.2022.03.005","article-title":"Schixator, a new FXa inhibitor from with antithrombotic effect and low bleeding risk","volume":"603","author":"Ding","year":"2022","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Bonturi, C.R., Teixeira, A.B.S., Rocha, V.M., Valente, P.F., Oliveira, J.R., Filho, C.M.B., Batista, I.F.C., and Oliva, M.L.V. (2022). Plant Kunitz Inhibitors and Their Interaction with Proteases: Current and Potential Pharmacological Targets. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23094742"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/B978-0-12-385504-6.00005-1","article-title":"Regulation of Proteases by Protein Inhibitors of the Serpin Superfamily","volume":"99","author":"Olson","year":"2011","journal-title":"Proteases Health Dis."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Jmel, M.A., Voet, H., Ara\u00fajo, R.N., Tirloni, L., S\u00e1-Nunes, A., and Kotsyfakis, M. (2023). Tick Salivary Kunitz-Type Inhibitors: Targeting Host Hemostasis and Immunity to Mediate Successful Blood Feeding. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24021556"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1007\/s00239-020-09959-9","article-title":"Evolutionary Aspects of the Structural Convergence and Functional Diversification of Kunitz-Domain Inhibitors","volume":"88","author":"Mishra","year":"2020","journal-title":"J. Mol. Evol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1182\/blood-2016-09-692996","article-title":"Emerging anticoagulant strategies","volume":"129","author":"Fredenburgh","year":"2017","journal-title":"Blood"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Chen, Z., Luo, F., Feng, J., Yang, W., Zeng, D., Zhao, R., Cao, Z., Liu, M., Li, W., and Jiang, L. (2013). Genomic and structural characterization of Kunitz-type peptide LmKTT-1a highlights diversity and evolution of scorpion potassium channel toxins. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0060201"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Zhao, R., Dai, H., Qiu, S., Li, T., He, Y., Ma, Y., Chen, Z., Wu, Y., Li, W., and Cao, Z. (2011). SdPI, the first functionally characterized Kunitz-type trypsin inhibitor from scorpion venom. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0027548"}],"container-title":["Toxins"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6651\/16\/10\/450\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:17:34Z","timestamp":1760113054000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6651\/16\/10\/450"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,21]]},"references-count":57,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2024,10]]}},"alternative-id":["toxins16100450"],"URL":"https:\/\/doi.org\/10.3390\/toxins16100450","relation":{},"ISSN":["2072-6651"],"issn-type":[{"type":"electronic","value":"2072-6651"}],"subject":[],"published":{"date-parts":[[2024,10,21]]}}}