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第十四届生物毒素毒理学术大会暨第一届生物毒素——从生存...

作者： Ding L Hao J Luo X Chen Z Department of Biochemistry and Molecular Biology Institute of Basic Medical SciencesCollege of Basic MedicineHubei University of Medicine Department of Clinical Laboratory Dongfeng HospitalHubei University of Medicine Department of Clinical Laboratory Shiyan Occupational Disease Hospital

Although there were a lot of weakly active animal toxins in the venoms,their values and applications are still mysterious,such as BF9,which is a kunitz-type toxin isolated from the venom of the elapid snake Bungarus ***,we used BF9 to be a molecular scaffold,and engineered eight BF9-derived peptides by changing P1 site Asn17 of BF9,such as BF9-N17 Y and BF9-N17 T designed from the polar subfamily,BF9-N17 L and BF9-N17 G designed from the Non-polar subfamily,BF9-N17 D designed from acidic subfamily,and BF9-N17 H,BF9-N17 K and BF9-N17 R designed from basic *** enzyme inhibitor experiment assays,we found a potent and selective chymotrypsin inhibitor BF9-N17 Y,a potent and selective coagulation factor XIa inhibitor BF9-N17 H,and two highly potent coagulation factor XIa inhibitors BF9-N17 K and *** and PT assays further showed that BF9-N17 H,BF9-N17 K and BF9-N17 R were three novel anticoagulants with selectively intrinsic coagulation pathway inhibitory *** that natural weakly active animal toxins are also a huge peptide resource,our present work might open a new window about pharmacological applications of weakly active animal toxins,which might be good templates for potent and selective molecular probe and lead drug designs.

关键词： Animal toxin kunitz-type Molecular design Peptide drug Protease inhibitor

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Characterization of a novel variant of the second domain of bikunin with increased leukocyte elastase inhibitory activity

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Journal of Biophysical Chemistry 2012年第2期3卷 132-141页

作者： Masaki Nakamura Takashi Takeuchi Yoshitaka Maeda Yoshitaka Hosaka Shoji Furusako Discovery Research Mochida Pharmaceutical Co. Ltd. Shizuoka Japan

The light chain of inter-α inhibitor, also known as bikunin or urinary trypsin inhibitor, is composed of two tandemly arranged kunitz-type protease inhibitor domains. The second domain of bikunin has factor Xa inhibitory activity which previously was enhanced by mutating two amino acids, glutamine 19 and tyrosine 46 to lysine and aspartate, respectively. In this study, we tried to potentiate its inhibitory activity against leukocyte elastase. A molecular docking model of the second domain of bikunin with leukocyte elastase revealed that P5 arginine 11 was a candidate residue for a third substitution. We generated six triple point mutants using site-directed mutagenesis, compared their leukocyte elastase-inhibitory activities, and selected the most potent variant with arginine 11 substituted to serine. The IC50 values for factor XIa, factor Xa, and leukocyte elastase were 182, 302, and 273 nM, respectively. Moreover, this triple point mutant prolonged the activated partial thromboplastin time and moderately reduced leukocyte elastase-induced endothelial injury. Additionally, favorable conformations created by these mutations were speculated using the structure of the kunitz protease inhibitor domain of protease nexin 2 complexed with factor XIa as a reference. We discovered a novel triple point mutant of the second domain of bikunin that has potent inhibitory activities against factor XIa, factor Xa, and leukocyte elastase. This variant exhibited anticoagulant activity in plasma and suppressed endothelial cell injury.

关键词： Inter-α Inhibitor Bikunin kunitz-type Protease Inhibitor Leukocyte Elastase Factor XIa

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The Kv1.3 channel-inhibitory toxin BF9 also displays anticoagulant activity via inhibition of factor XIa

The Kv1.3 channel-inhibitory toxin BF9 also displays anticoa...

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第十四届生物毒素毒理学术大会暨第一届生物毒素——从生存...

The Kvl.3 channel plays potential roles in immune,inflammation and coagulation *** studies showed that Kv1.3 channel inhibitors have immunosuppressive and anti-inflammatory activities,but no Kv1.3 channel inhibitors have been found to have anticoagulation ***,based on our previous work about Kv1.3 channel toxin peptide inhibitors,we first attempt to test anticoagulation activities of four known venom-derived Kvl.3 channel inhibitors with different structural folds:BmKTX with CSα/β structural fold,OmTx3 with CSα/α structural fold,BF9 with Kuntz-type structural fold,and SjAPI-2 with Ascaris-type structural *** results showed that BmKTX and OmTx3 have no activities towards both intrinsic and extrinsic coagulation pathway,SjAPI-2 just has weak activity towards intrinsic coagulation pathway,and BF9 has potent activity towards intrinsic coagulation pathway with no apparent effect on extrinsic coagulation *** and inhibitor reaction kinetics experiments further showed that BF9 inhibited intrinsic coagulation pathway-associated coagulation factor XIa,but have no apparent effects on common coagulation pathway coagulation factor ***-activity relationship showed that Gly14,Asn17,Ala18 and Ile20 of BF9 are main residues involved in the inhibiting effect on factor *** the best of our knowledge,BF9 is the first anticoagulant with Kvl.3 channel inhibitory ***,our present studies found the first dual functional peptides with Kv1.3 channel and coagulation factor XIa inhibitory activities,and provided a new molecular template for the lead drug discovery towards immune and thrombosis-associated human diseases.

关键词： Anticoagulation Factor XIa kunitz-type Kv1.3 channel Structural fold

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