Development of a novel anti-platelet drug targeted for collagen-induced platelet aggregation

开发针对胶原诱导的血小板聚集的新型抗血小板药物

• 批准号: 24659460
• 负责人: YOSHIDA Shigeto
• 金额: $ 2.33万
• 依托单位: Kanazawa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Challenging Exploratory Research
• 财政年份: 2012
• 资助国家: 日本
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-24659460/
• 关键词: 抗血小板薬; コラーゲン; ハマダラカ; 唾液タンパク; 結晶構造

AAPP, a mosquito saliva protein, specifically blocks platelet adhesion to collagen by binding directly to collagen and subsequently causing platelet aggregation. The aim of this study was to identify the active region of AAPP responsible for the anti-thrombotic activity because we hypothesized that AAPP could be used as a candidate anti-platelet drug. We identified that the essential moiety of AAPP for collagen binding and anti-thrombotic activity was in the region encoded by exon 3-4. The crystal structure of this domain was also determined. AAPP inhibited whole blood aggregation induced by collagen at 10 mg/kg body weight. AAPP prevented pulmonary death at a lower dose (3 mg/kg) without prolongation of bleeding time compared with aspirin (100 mg/kg) that compromised hemostasis. These results indicate that AAPP has great potential as a new anti-platelet agent with a better risk/benefit ratio than that seen with aspirin.

AAPP是一种蚊子唾液蛋白，通过直接与胶原蛋白结合并随后引起血小板聚集来特异性地阻断血小板与胶原蛋白的粘附。本研究的目的是确定AAPP的活性区域负责抗血栓活性，因为我们假设AAPP可以作为一个候选的抗血小板药物。我们确定AAPP的胶原结合和抗血栓活性的基本部分是在外显子3-4编码的区域。并测定了该畴的晶体结构。AAPP在10 mg/kg体重时抑制胶原诱导的全血聚集。与阿司匹林（100 mg/kg）相比，AAPP在较低剂量（3 mg/kg）下可预防肺死亡，而不会延长出血时间，因为阿司匹林会影响止血。这些结果表明，AAPP作为一种新的抗血小板药物具有很大的潜力，其风险/效益比优于阿司匹林。

项目成果

Visualization and live imaging analysis of a mosquito saliva protein in host animal skin using a transgenic mosquito with a secreted luciferase reporter system

• DOI: 10.1111/imb.12055
• 发表时间: 2013-12-01
• 期刊: INSECT MOLECULAR BIOLOGY
• 影响因子: 2.6
• 作者: Yamamoto, D. S.;Yokomine, T.;Yoshida, S.
• 通讯作者: Yoshida, S.

Identification of the active region responsible for the anti-thrombotic activity of anopheline anti-platelet protein from a malaria vector mosquito

• DOI: 10.3109/09537104.2012.698430
• 发表时间: 2013-01-01
• 期刊: PLATELETS
• 影响因子: 3.3
• 作者: Hayashi, Hideki;Kyushiki, Hiroyuki;Yoshida, Shigeto
• 通讯作者: Yoshida, Shigeto

The Crystal Structure of the Active Domain of Anopheles Anti-platelet Protein, a Powerful Anti-coagulant, in Complex with an Antibody*

• DOI: 10.1074/jbc.m114.564526
• 发表时间: 2014-04
• 期刊: The Journal of Biological Chemistry
• 作者: K. Sugiyama;M. Iyori;Asuka Sawaguchi;S. Akashi;J. Tame;Sam-Yong Park;S. Yoshida

2種の蚊由来唾液タンパクにおける生物学的機能比較

两种蚊源唾液蛋白的生物学功能比较

• 发表时间: 2013
• 作者: Masatoshi Sakurai;Hiroyoshi Kunimoto;Naohide Watanabe;Yumi Fukuchi;Shinsuke Yuasa;Keiichi Fukuda;Satoshi Yamazaki;Hiromitsu Nakauchi;Yasuhiro Ebihara;Koichiro Tsuji;Etsuro Ito;Yuka Harada;Hironori Harada;Shinichiro Okamoto;Hideaki Nakajima;伊従光洋,澤口明日香,吉田栄人
• 通讯作者: 伊従光洋,澤口明日香,吉田栄人

「Vector-borne diseases研究 : ラボからフィールドへ」トランスジェニック蚊を用いたマラリア原虫−唾液腺相互作用の解明

“媒介传播疾病研究：从实验室到现场”利用转基因蚊子阐明疟疾寄生虫与唾液腺的相互作用

• 发表时间: 2013
• 作者: Eri Matsuki;Taku Kikuchi;Norisato Hashimoto;Shunsuke Souma;Sumiko Kohashi;Takaaki Toyama;Masatoshi Sakurai;Daiki Karigane;Daichi Abe;Takayuki Shimizu;Kenji Yokoyama;Hideaki Nakajima;Shinichiro Okamoto;吉田栄人
• 通讯作者: 吉田栄人