An anticoagulant peptide from the human hookworm, <i>Ancylostoma duodenale</i> that inhibits coagulation factors Xa and XIa

Gan, Weiqiong; Deng, Li; Yang, Chen; He, Qingfeng; Hu, Jingjing; Yin, Han; Jin, Xian; Lu, Chengyu; Wu, Yamin; Peng, Lifei

doi:10.1016/j.febslet.2009.05.009

Cited by 32 publications

(31 citation statements)

References 21 publications

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“…The TIL domain inhibitors were first identified in Ascaris suum and Ascaris lumbricoides (Peanasky et al 1984a, b;Babin et al 1984;Grasberger et al 1994) and widely distributed in nematodes. Several anticoagulant serine protease inhibitors with a single TIL domain have been previously identified in Ancylostoma duodenale (Gan et al 2009) and in the related hookworm Ancylostoma caninum and Ancylostoma ceylanicum (Stassens et al 1996;Harrison et al 2002;Mieszczanek et al 2004a, b;Deng et al 2010). In this study, we described the isolation, identification, and characterization of a two-TIL domain serine protease inhibitor, AduTIL-1, from the human hookworm Ancylostoma duodenale (Milstone et al 2000).…”

Section: Discussionmentioning

confidence: 92%

“…The anticoagulant inhibitors, which contain a single TIL domain from the hookworm Ancylostoma caninum, Ancylostoma ceylanicum, and Ancylostoma duodenale, may be utilized to maintain the flow of blood to facilitate bleeding (Stassens et al 1996;Harrison et al 2002;Mieszczanek et al 2004a, b;Gan et al 2009;Deng et al 2010). However, AduTIL-1, with 2-TIL domain, has no detectable anticoagulant activity (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…1994;Nguyen et al 1999;Boag et al 2002;Ford et al 2005). These TIL domain inhibitors are believed to protect parasites from the host digestive enzymes (Peanasky et al 1984a, b;Babin et al 1984;Grasberger et al 1994) and to facilitate feeding (Stassens et al 1996;Harrison et al 2002;Mieszczanek et al 2004a, b;Gan et al 2009;Deng et al 2010), as well as to be involved in embryogenesis and spermatogenesis (Ford et al 2005).…”

Section: Introductionmentioning

confidence: 94%

“…The Ancylostoma ceylanicum Kunitz-type inhibitor 1 (AceKI-1), which is an inhibitor of chymotrypsin, pancreatic elastase, neutrophil elastase, and trypsin, may play roles in the parasite's survival and pathogenesis of hookworm-associated malnutrition (Milstone et al 2000;Chu et al 2004). However, in addition to AduNAP4, an inhibitor of both fXa and fXIa (Gan et al 2009), little is known of the protease inhibitors in the predominant human hookworm Ancylostoma duodenale.…”

Section: Introductionmentioning

confidence: 98%

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Identification and characterization of a serine protease inhibitor with two trypsin inhibitor-like domains from the human hookworm Ancylostoma duodenale

Jin

Deng

et al. 2010

Parasitol Res

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Protease inhibitors play important roles in the parasitic nematodes' survival within their host, in the development and reproduction of the parasites. The present study described the isolation, identification, and characterization of a novel member of the Ascaris family of serine protease inhibitors, designated AduTIL-1, from the human hookworm Ancylostoma duodenale. AduTIL-1 is composed of a signal sequence and two trypsin inhibitor-like (TIL) domains, which showed the highest similarity with OdmCRP, a putative serine protease inhibitor with two TIL domains in Oesophagostomum dentatum. Each TIL domain of the AduTIL-1 was expressed in Escherichia coli, and their inhibitory activities against serine proteases from animals and human were characterized, respectively. Both of the two TIL domains inhibited human neutrophil elastase and pancreatic trypsin, but different in effectiveness. Although the first TIL domain of AduTIL-1 inhibited bovine pancreatic chymotrypsin (Ki=18.0 nM), both of the two domains showed no inhibitory activity against the human pancreatic chymotrypsin. Immunohistochemical studies demonstrated that AduTIL-1 was localized in esophagus, intestine, and cuticular surface of the adult worms. These results suggested that AduTIL-1 may be involved in the survival of A. duodenale in host by targeting related digestive enzymes and neutrophil elastase.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 98%

See 2 more Smart Citations

Identification and characterization of a serine protease inhibitor with two trypsin inhibitor-like domains from the human hookworm Ancylostoma duodenale

Jin

Deng

et al. 2010

Parasitol Res

Self Cite

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“…A hookworm platelet inhibitor (HPI) has also been purified and cloned from adult A. caninum that targets the major integrin receptors responsible for adhesion to collagen (GPIa/IIa) and fibrinogen (GPIIb/IIIa) [39]. The recent cloning of two hookworm inhibitors of fXIa, (AduNAP4, AcaNAP10), as well as a fourth fXa inhibitor (Ac-AP-12) further expands the anticoagulant portfolio of hematophagous nematodes [40][41][42]. The fact that hookworms have evolved multiple mechanisms to interfere with host blood clotting affirms a critical role for bloodfeeding in parasite biology, and validates these molecules as legitimate targets for drug and/or vaccine development.…”

Section: Hookworm Virulence Factors and Disease Pathogenesismentioning

confidence: 98%

Twenty-First Century Progress Toward the Global Control of Human Hookworm Infection

Bungiro

Cappello

2011

Curr Infect Dis Rep

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Hookworms are bloodsucking nematodes that afflict up to 740 million persons in tropical and subtropical regions, with Asia and sub-Saharan Africa exhibiting particularly high infection rates. Prevalence, intensity, and pathology often vary considerably at both the regional and local level, and may be influenced by coinfection with other parasitic infections such as malaria. Immunoepidemiological studies suggest that hookworms manipulate the host immune response and may provide some protection from allergy and asthma. There has been substantial progress in elucidating the molecular pathogenesis of hookworm disease, with anticoagulants, protease inhibitors, digestive proteases, and novel excretory/secretory proteins being of particular interest. Mass chemotherapy remains a mainstay of hookworm control strategies, although continued use of drugs may lead to reduced efficacy and treatment failures have been observed. Consequently, a need exists for innovative approaches, such as vaccination; recent studies have identified and/or evaluated candidate vaccine antigens in human and animal models.

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The Discovery of New Human Coagulation Factor XIa (FXIa) Inhibitors by Synthesis, Biological Evaluation, and Structure‐based Modeling

Lee

Song²,

Kim³

et al. 2016

Bulletin Korean Chem Soc

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Factor XIa (FXIa) is an enzyme that is activated during the earliest stage of initiation of the intrinsic pathway of the blood coagulation mechanism. In this study, we attempted to discover a new FXIa inhibitor based on structure-based molecular modeling. We found that compound 16 exhibits satisfactory predicted properties while maintaining important binding interactions with FX1a. ExperimentalDocking Study. To find a new FX1a inhibitor, we carried out a docking study of selected molecules using the § Contributed equally to this work. Procedure for the Synthesis of 4-(3-Azido-2-benzylpropanamido)-Benzoic Acid Methyl Ester (Scheme 4).2-Benzyl-3-hydroxypropanoic acid, 12 (5 g, 27.70 mmol) in DCM (200 mL) was added to t-butyldimethylsilyl chloride (9.2 g, 61.0 mmol) and imidazole (8.5 g, 124.70 mmol), stirred for 5 h, and extracted, and then ammonium chloride was added (20 mL) and again extracted with DCM (20 mL × 2). After LiOH (554 mg, 13.2 mmol) was added, the reaction mixture was stirred for 2 h, extracted with ethyl acetate (20 mL × 2), recrystallized with diethyl ether (5 mL), and 13 (8.7 mg, 99%) was obtained. And then, DIPEA (188 μL, 1.08 mmol) and PyBOP (2.3 g, 4.40 mmol) were added to 13 (1 g, 3.39 mmol) in DCM (20 mL). This solution was stirred for 6 h, and the reaction mixture was extracted with ethyl acetate (20 mL × 2). TBAF (0.5 mL, 0.48 mmol) was added Scheme 2. Synthesis of tert-butyl (1-azido-3-phenylpropan-2-yl) carbamate. (a) Ms 2 O, TEA, NaN 3 , rt. Scheme 3. Synthesis of compounds 9-11. (a) (1-Azidomethyl-3-methyl-pent-3-enyl)-carbamic acid tert-butyl ester, CuSO 4 , sodium ascorbate, DMSO:H 2 O, rt; (b) 4 M HCl, DCM, rt; (d) p-R-benzoic acid, PyBOP, DIPEA, DMF, rt. Scheme 6. Synthesis of benzyl-(2-hydroxyimino-ethyl)-carbamic acid tert-butyl ester/(2-hydroxyimino-ethyl)-phenethyl-carbamic acid tert-butyl ester. (a) Ethyl

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An anticoagulant peptide from the human hookworm, Ancylostoma duodenale that inhibits coagulation factors Xa and XIa

Cited by 32 publications

References 21 publications

Identification and characterization of a serine protease inhibitor with two trypsin inhibitor-like domains from the human hookworm Ancylostoma duodenale

Identification and characterization of a serine protease inhibitor with two trypsin inhibitor-like domains from the human hookworm Ancylostoma duodenale

Twenty-First Century Progress Toward the Global Control of Human Hookworm Infection

The Discovery of New Human Coagulation Factor XIa (FXIa) Inhibitors by Synthesis, Biological Evaluation, and Structure‐based Modeling

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