Development of protease inhibitor drugs to treat Alzheimer's disease

描述（由申请人提供）：目前还没有药物可以阻止阿尔茨海默病（AD）的进展。神经中毒？淀粉样肽（A？？）被认为是导致这种疾病的原因，其在大脑斑块中的积累是一个标志。一个？是由一种较大的淀粉样前体蛋白（APP）裂解的蛋白酶，称为？然后呢？分泌酶抑制的化合物？-分泌酶可能通过减少A β的产生来阻止疾病的进展。 CA 074 Me和loxistatin（也称为E64 d或EST）是半胱氨酸蛋白酶抑制剂，并且半胱氨酸蛋白酶组织蛋白酶B是受调节的分泌途径中的候选2-分泌酶。这些化合物对脑β-分泌酶的抑制作用可能是由于对组织蛋白酶B？- 分泌酶活性。尽管洛昔他汀已被证明可安全用于人类，但该化合物的非特异性结合和结构相似的CA 074 Me可能限制其治疗用途。 可逆蛋白酶抑制剂作为AD治疗剂提供了潜在的药理学优势。因此，这项资助将开发可逆的小分子组织蛋白酶B抑制剂，并确定其在各种AD模型中的疗效。已发表的数据表明，可逆的拟肽组织蛋白酶B抑制剂，Ac-LVK-CHO，减少脑A？大脑？在豚鼠模型中的分泌酶活性，使得在该资助中开发的可逆性组织蛋白酶B抑制剂可能是有效的。如果成功的话，这项工作将带来一类新的AD疗法，可能对治疗这种可怕的疾病产生重大影响。公共卫生相关性：该项目与公共卫生的相关性是开发新的有效的阿尔茨海默病药物。目前，还没有有效的手段来阻止这种毁灭性疾病的进展，迫切需要新的药物。该项目可能导致药物停止或可能逆转AD的进展。

DESCRIPTION (provided by applicant): There currently is no drug available that stops the progression of Alzheimer's disease (AD). Neurotoxic ?-amyloid peptides (A??) are thought to cause the disease with their accumulation in brain plaques being a hallmark. A? are cleaved from a larger amyloid precursor protein (APP) by proteases, called ?? and ?-secretases. Compounds that inhibit ?-secretase may stop the progression of the disease by reducing the production of A?. CA074Me and loxistatin (also known as E64d or EST) are cysteine protease inhibitors and the cysteine protease, cathepsin B, is a candidate 2-secretase in the regulated secretory pathway. The inhibiton of brain 2-secretase by these compounds is likely due to inhibition of cathepsin B ? -secretase activity. Although loxistatin has been shown safe to use in humans, non-specific binding by this compound, and the structurally similar CA074Me, may limit their therapeutic use. Reversible protease inhibitors offer potential pharmacological advantages as AD therapeutics. This grant, therefore, will develop reversible, small molecule, cathepsin B inhibitors and determine their efficacy in various AD models. Published data show that the reversible peptidomimetic cathepsin B inhibitor, Ac-LVK-CHO, reduces brain A? and brain ?-secretase activity in the guinea pig model, making it likely that the reversible cathepsin B inhibitors developed in this grant will be efficacious. If successful, the work will usher in a new class of AD therapeutics that could have a major impact on treating this dreadful disease. PUBLIC HEALTH RELEVANCE: The relevance of this project to the public health is the development of new and effective Alzheimer's disease drugs. Currently, there is no effective means of stopping the progress of this devastating disease and there is an urgent need for new drugs that do so. This project may result in drugs that halt or, possibly, reverse the progression of AD.