Influence of Steric Shield on Biocompatibility and Antithrombotic Activity of Dendritic Polyphosphate Inhibitor.
Influence of Steric Shield on Biocompatibility and Antithrombotic Activity of Dendritic Polyphosphate Inhibitor.
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空间屏障对树枝状聚磷酸盐抑制剂生物相容性和抗血栓活性的影响。
DOI：
10.1021/acs.molpharmaceut.1c00934
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发表时间：
2022-06-06
影响因子：
4.9
通讯作者：
Kizhakkedathu, Jayachandran N.
中科院分区：
文献类型：
--
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.
关键词：
聚阴离子，无机聚磷酸盐（polyP），是一种促凝血分子，已成为一个有前途的治疗目标，在抗血栓药物的发展。使用聚阳离子抑制剂中和聚P的促血栓活性是设计新的聚P抑制剂的可行策略之一。然而，在这种方法中，需要聚P和抑制剂的静电相互作用之间的精细平衡。已知任何未受保护的聚阳离子与带负电荷的血液成分相互作用，可能导致血小板活化、细胞毒性和出血。因此，设计具有良好生物相容性的有效聚阳离子聚P抑制剂是一个重大挑战。基于我们以前对通用肝素逆转剂（UHRA）的研究，我们报告了具有改进的空间屏蔽设计的聚P抑制剂。改变分子量、阳离子结合基团的数量和聚乙二醇（PEG）链的长度以获得所需的抑制剂。我们研究了聚甘油支架上的两种不同PEG长度（mPEG-750与mPEG-350），并研究了它们对生物相容性和聚P中和活性的影响。具有mPEG-750刷层的聚P抑制剂mPEG 750 UHRA-10通过许多测量参数显示出与其mPEG-350类似物相比具有上级生物相容性，而不丧失其中和活性。阳离子结合基团的增加（mPEG 750 UHRA-8中为25个基团，mPEG 750 UHRA-10 [HC]中为32个基团）未改变中和活性，这表明mPEG-750屏蔽层可显著保护阳离子结合基团，从而有助于最大限度地减少不必要的非特异性相互作用。此外，与先前用作聚P抑制剂的常规聚阳离子（例如，PAMAM树枝状聚合物和聚乙烯亚胺）。通过这项研究，我们证明了空间屏蔽设计对高度生物相容性聚P抑制剂的重要性。这种方法可用于设计高度生物相容的大分子抑制剂。
The polyanion, inorganic polyphosphate (polyP), is a procoagulant molecule which has become a promising therapeutic target in the development of antithrombotics. Neutralizing polyP’s prothrombotic activity using polycationic inhibitors is one of the viable strategies to design new polyP inhibitors. However, in this approach, a fine balance between the electrostatic interaction of polyP and the inhibitor is needed. Any unprotected polycations are known to interact with negatively charged blood components, potentially resulting in platelet activation, cellular toxicity, and bleeding. Thus, designing potent polycationic polyP inhibitors with good biocompatibility is a major challenge. Building on our previous research on universal heparin reversal agent (UHRA), we report polyP inhibitors with a modified steric shield design. The molecular weight, number of cationic binding groups, and the length of the polyethylene glycol (PEG) chains were varied to arrive at the desired inhibitor. We studied two different PEG lengths (mPEG-750 versus mPEG-350) on the polyglycerol scaffold and investigated their influence on biocompatibility and polyP neutralization activity. The polyP inhibitor with mPEG-750 brush layer, mPEG750 UHRA-10, showed superior biocompatibility compared to its mPEG-350 analogs by a number of measured parameters without losing its neutralization activity. An increase in cationic binding groups (25 groups in mPEG750 UHRA-8 and 32 in mPEG750 UHRA-10 [HC]) did not alter the neutralization activity, which suggested that the mPEG-750 shield layer provides significant protection of cationic binding groups and thus helps to minimize unwanted nonspecific interactions. Furthermore, these modified polyP inhibitors are highly biocompatible compared to conventional polycations that have been previously used as polyP inhibitors (e.g., PAMAM dendrimers and polyethylenimine). Through this study, we demonstrated the importance of the design of steric shield toward highly biocompatible polyP inhibitors. This approach can be exploited in the design of highly biocompatible macromolecular inhibitors.
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Kalathottukaren, Manu T.;Creagh, A. Louise;Haynes, Charles
通讯作者：
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影响因子：
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