Smart thrombosis inhibitors without bleeding side effects via charge tunable ligand design.
Smart thrombosis inhibitors without bleeding side effects via charge tunable ligand design.
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DOI：
10.1038/s41467-023-37709-0
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发表时间：
2023-04-26
影响因子：
16.6
通讯作者：
Kizhakkedathu, Jayachandran N.
中科院分区：
文献类型：
--
作者：
La, Chanel C.;Smith, Stephanie A.;Vappala, Sreeparna;Adili, Reheman;Luke, Catherine E.;Abbina, Srinivas;Luo, Haiming D.;Chafeeva, Irina;Drayton, Matthew;Creagh, Louise A. A.;de Guadalupe Jaraquemada-Pelaez, Maria;Rhoads, Nicole;Kalathottukaren, Manu Thomas;Henke, Peter K.;Straus, Suzana K.;Du, Caigan;Conway, Edward M.;Holinstat, Michael;Haynes, Charles A.;Morrissey, James H.;Kizhakkedathu, Jayachandran N.
目前预防血栓形成的治疗方法，即抗凝剂和血小板拮抗剂，仍然存在持续出血的风险。改善治疗策略，减少这种风险将有巨大的临床影响。中和和抑制多磷酸盐（polyP）的抗血栓形成剂可以是实现这样的目标的有力方法。在这里，我们报告了一个设计概念对聚P抑制，称为大分子聚阴离子抑制剂（MPI），具有高结合亲和力和特异性。通过在生理pH下具有低电荷密度但在与聚P结合时增加其电荷的分子的文库筛选来鉴定先导抗血栓候选物，从而提供了增强其活性和选择性的智能方式。主要MPI候选物在小鼠血栓形成模型中显示出抗血栓形成活性，不会引起出血，并且即使在非常高的剂量下在小鼠中也具有良好的耐受性。预计开发的抑制剂将为预防血栓形成开辟道路，而不会有出血风险，这是目前治疗方法无法解决的挑战。预防血栓形成的治疗是次优的。在这里，作者确定了一种基于阴离子结合基团的可切换质子化状态的靶向多磷酸盐的抗血栓形成药物，在多种小鼠模型中证明了抗血栓形成活性，不引起出血，并且耐受性良好。
Current treatments to prevent thrombosis, namely anticoagulants and platelets antagonists, remain complicated by the persistent risk of bleeding. Improved therapeutic strategies that diminish this risk would have a huge clinical impact. Antithrombotic agents that neutralize and inhibit polyphosphate (polyP) can be a powerful approach towards such a goal. Here, we report a design concept towards polyP inhibition, termed macromolecular polyanion inhibitors (MPI), with high binding affinity and specificity. Lead antithrombotic candidates are identified through a library screening of molecules which possess low charge density at physiological pH but which increase their charge upon binding to polyP, providing a smart way to enhance their activity and selectivity. The lead MPI candidates demonstrates antithrombotic activity in mouse models of thrombosis, does not give rise to bleeding, and is well tolerated in mice even at very high doses. The developed inhibitor is anticipated to open avenues in thrombosis prevention without bleeding risk, a challenge not addressed by current therapies. Treatments to prevent thrombosis are suboptimal. Here, the authors identify a lead an antithrombotic drug targeting polyphosphate based on switchable protonation states for the anion-binding groups, demonstrating antithrombotic activity in multiple mouse models, not causing bleeding, and well tolerated.
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DOI：
10.1056/nejmoa1405760
发表时间：
2015-01-15
期刊：
The New England journal of medicine
影响因子：
--
作者：
Büller HR;Bethune C;Bhanot S;Gailani D;Monia BP;Raskob GE;Segers A;Verhamme P;Weitz JI;FXI-ASO TKA Investigators
通讯作者：
FXI-ASO TKA Investigators
DOI：
10.1161/atvbaha.117.309868
发表时间：
2017-10
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Adili R;Tourdot BE;Mast K;Yeung J;Freedman JC;Green A;Luci DK;Jadhav A;Simeonov A;Maloney DJ;Holman TR;Holinstat M
通讯作者：
Holinstat M
影响因子：
2.9
作者：
Antosiewicz, J;McCammon, JA;Gilson, MK
通讯作者：
Gilson, MK
影响因子：
4.9
作者：
Abbina, Srinivas;La, Chanel C.;Vappala, Sreeparna;Kalathottukaren, Manu Thomas;Abbasi, Usama;Gill, Arshdeep;Smith, Stephanie A.;Haynes, Charles A.;Morrissey, James H.;Kizhakkedathu, Jayachandran N.
通讯作者：
Kizhakkedathu, Jayachandran N.
影响因子：
7.3
作者：
Graffner-Nordberg, M;Marelius, J;Hallberg, A
通讯作者：
Hallberg, A