Development of protease inhibitor drugs to treat Alzheimer's disease

描述（由申请人提供）：目前没有可用的药物可以阻止阿尔茨海默病（AD）的进展。神经毒性?-淀粉样肽（A??）被认为是导致这种疾病的原因，它们在脑斑块中的积累是一个标志。一个吗?由一个更大的淀粉样前体蛋白（APP）被蛋白酶(称为？？和? -secretases。抑制？-分泌酶可能通过减少A?的产生来阻止疾病的进展。CA074Me和洛司他汀（也称为E64d或EST）是半胱氨酸蛋白酶抑制剂，半胱氨酸蛋白酶组织蛋白酶B是调节分泌途径中的候选2-分泌酶。这些化合物对脑2-分泌酶的抑制可能是由于对组织蛋白酶B的抑制。分泌酶的活动。虽然洛司他汀已被证明在人体中使用是安全的，但这种化合物的非特异性结合，以及结构类似的CA074Me，可能限制了它们的治疗用途。可逆性蛋白酶抑制剂作为AD治疗药物具有潜在的药理优势。因此，这笔拨款将用于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。已发表的数据显示，可逆的拟肽组织蛋白酶B抑制剂Ac-LVK-CHO可降低脑A？大脑呢？-分泌酶在豚鼠模型中的活性，使得这项资助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，这项工作将迎来一类新的阿尔茨海默病治疗方法，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发展，因此迫切需要能够阻止这种疾病的新药。这个项目可能会产生阻止或可能逆转阿尔茨海默病进展的药物。

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.