Beta-sheet breaker peptide inhibitor of Alzheimer's amyloidogenesis with increased blood-brain barrier permeability and resistance to proteolytic degradation in plasma.
Beta-sheet breaker peptide inhibitor of Alzheimer's amyloidogenesis with increased blood-brain barrier permeability and resistance to proteolytic degradation in plasma.
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DOI：
10.1002/(sici)1097-4695(19990605)39:3
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发表时间：
1999-06
期刊：
影响因子：
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通讯作者：
J. Poduslo;G. Curran;Asok Kumar;Blas Frangione;Claudio Soto
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文献类型：
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作者：
J. Poduslo;G. Curran;Asok Kumar;Blas Frangione;Claudio Soto
与Abeta中心区域同源但含有脯氨酸残基作为β -片阻滞剂的短合成肽已在体外被证明与Abeta高亲和力结合，部分抑制Abeta纤维形成，并重新溶解预先形成的原纤维。虽然短肽在医学上被广泛用作治疗药物，但与它们在中枢神经系统疾病中的应用相关的两个重要问题必须得到解决：(a)血浆中蛋白质的快速水解降解，(b)血脑屏障（BBB）渗透性差。最近，我们已经证明，蛋白质与天然存在的多胺的共价修饰显着增加了它们在血脑屏障的通透性。我们已经将这项技术扩展到iAbeta11，这是一种抑制Abeta纤维形成的11-残基β -片破片肽，通过多胺，腐胺（PUT）共价修饰该肽，并评估其血浆药代动力学和血脑屏障通透性。采用三氯乙酸（TCA）沉淀法和纸层析法测定，大鼠单次静脉注射后，125I-YiAbeta11和125I-PUT-YiAbeta11均在血浆中快速降解。通过切换到YiAbeta11和PUT-YiAbeta11的所有d -对映体，在静脉注射后15分钟，大鼠血浆蛋白酶的降解率分别为1.9%和5.7%，具有显著的保护作用。与125i - putd - yiabeta11相比，125i - putd - yiabeta11在脑屏障的通透系数x表面积积在皮质和海马中高出5 - 7倍，而剩余血浆体积无显著差异。体外实验表明，PUT-D-YiAbeta11保留了部分抑制β纤维形成和溶解预先形成的淀粉样原纤维的能力。由于其血脑屏障通透性增加了5到7倍，并且在血浆中具有抗蛋白质水解的能力，这种多胺修饰的β -破片肽可能被证明是体内淀粉样蛋白形成的有效抑制剂，因此是治疗阿尔茨海默病的重要方法。
Short synthetic peptides homologous to the central region of Abeta but bearing proline residues as beta-sheet blockers have been shown in vitro to bind to Abeta with high affinity, partially inhibit Abeta fibrillogenesis, and redissolve preformed fibrils. While short peptides have been used extensively as therapeutic drugs in medicine, two important problems associated with their use in central nervous system diseases have to be addressed: (a) rapid proteolytic degradation in plasma, and (b) poor blood-brain barrier (BBB) permeability. Recently, we have demonstrated that the covalent modification of proteins with the naturally occurring polyamines significantly increases their permeability at the BBB. We have extended this technology to iAbeta11, an 11-residue beta-sheet breaker peptide that inhibits Abeta fibrillogenesis, by covalently modifying this peptide with the polyamine, putrescine (PUT), and evaluating its plasma pharmacokinetics and BBB permeability. After a single intravenous bolus injection in rats, both 125I-YiAbeta11 and 125I-PUT-YiAbeta11 showed rapid degradation in plasma as determined by trichloroacetic acid (TCA) precipitation and paper chromatography. By switching to the all D-enantiomers of YiAbeta11 and PUT-YiAbeta11, significant protection from degradation by proteases in rat plasma was obtained with only 1.9% and 5.7% degradation at 15 min after intravenous bolus injection, respectively. The permeability coefficient x surface area product at the BBB was five- sevenfold higher in the cortex and hippocampus for the 125I-PUT-D-YiAbeta11 compared to the 125I-D-YiAbeta11, with no significant difference in the residual plasma volume. In vitro assays showed that PUT-D-YiAbeta11 retains its ability to partially inhibit Abeta fibrillogenesis and dissolve preformed amyloid fibrils. Because of its five- to sevenfold increase in permeability at the BBB and its resistance to proteolysis in the plasma, this polyamine-modified beta-sheet breaker peptide may prove to be an effective inhibitor of amyloidogenesis in vivo and, hence, an important therapy for Alzheimer's disease.