A Biomimetic of Endogenous Tissue Inhibitors of Metalloproteinases: Inhibition Mechanism and Contribution of Composition, Polymer Size, and Shape to the Inhibitory Effect
A Biomimetic of Endogenous Tissue Inhibitors of Metalloproteinases: Inhibition Mechanism and Contribution of Composition, Polymer Size, and Shape to the Inhibitory Effect
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DOI：
10.1021/acs.nanolett.1c01357
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发表时间：
2021-06-28
期刊：
影响因子：
10.8
通讯作者：
Shea, Kenneth J.
中科院分区：
文献类型：
--
作者：
Nakamoto, Masahiko;Escalante, Teresa;Shea, Kenneth J.
通过向合成四聚物中引入三个结合元件，设计了金属蛋白酶内源性组织抑制剂（TIMP）的仿生体。我们评估了 TIMP 模拟聚合物的组成、大小和形状对 BaP1（一种 P-I 类蛇毒金属蛋白酶 (SVMP)）抑制的贡献。当线性聚合物（LP）的尺寸与酶的尺寸相当或更大时，就实现了抑制，这表明功效需要与活性位点附近的酶表面的大部分结合。尽管尺寸和形状存在差异，但分子量显着更高的低交联聚合物水凝胶纳米颗粒 (NP) 的功效与 LP 相当，这对于体内应用来说是一个重要发现。非生物 TIMP 对全蛇毒液中的两类 SVMP 有效。该结果可以作为仿生聚合物酶抑制剂的设计原理。
A biomimetic of endogenous tissue inhibitors of metall-oproteinases (TIMPs) was engineered by introducing three binding elements to a synthetic tetrapolymer. We evaluated the contribution of composition, size, and shape of the TIMP-mimicking polymers to the inhibition of BaP1, a P-I class snake venom metalloproteinase (SVMP). Inhibition was achieved when the size of the linear polymer (LP) was comparable to or greater than that of the enzyme, indicating the efficacy requires binding to a significant portion of the enzyme surface in the vicinity of the active site. The efficacy of a low crosslinked polymer hydrogel nanoparticle (NP) of substantially greater molecular weight was comparable to that of the LPs despite differences in size and shape, an important finding for in vivo applications. The abiotic TIMP was effective against two classes of SVMPs in whole snake venom. The results can serve as a design principle for biomimetic polymer inhibitors of enzymes.