Development of protease inhibitor drugs to treat Alzheimer's disease

描述(申请人提供)：目前还没有阻止阿尔茨海默病(AD)进展的药物。神经毒性？-淀粉样多肽(A？？)被认为是导致这种疾病的原因，它们在大脑斑块中的堆积是一个标志。一个?被称为？？的酶从较大的淀粉样前体蛋白(APP)中裂解出来然后呢？-秘密。抑制β-分泌酶的化合物可能通过减少A？的产生来阻止疾病的进展。CA074Me和loxistatin(也称为E64d或EST)是半胱氨酸蛋白酶抑制剂，而半胱氨酸蛋白酶组织蛋白酶B是调节分泌途径的候选2-分泌酶。这些化合物对脑2-分泌酶的抑制作用可能是由于抑制了组织蛋白酶B-分泌酶的活性。尽管loxistatin已被证明在人类中使用是安全的，但这种化合物的非特异性结合，以及结构上相似的CA074Me，可能会限制它们的治疗用途。可逆酶抑制剂作为阿尔茨海默病的治疗药物具有潜在的药理优势。因此，这笔赠款将开发可逆的小分子组织蛋白酶B抑制剂，并确定它们在各种AD模型中的疗效。已发表的数据表明，可逆类肽类组织蛋白酶B抑制剂Ac-LVK-CHO能降低大脑A？以及在豚鼠模型中的脑分泌酶活性，这使得在这项授权中开发的可逆组织蛋白酶B抑制剂可能是有效的。如果成功，这项工作将带来一种新的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，没有有效的方法来阻止这种毁灭性疾病的进展，迫切需要能够做到这一点的新药。这一项目可能会导致药物阻止或可能逆转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.