Macrocyclic Immunoproteasome Inhibitors as a Potential Therapy for Alzheimer’s Disease

Previously,
we reported that immunoproteasome (iP)-targeting linear
peptide epoxyketones improve cognitive function in mouse models of
Alzheimer’s disease (AD) in a manner independent of amyloid
β. However, these compounds’ clinical prospect for AD
is limited due to potential issues, such as poor brain penetration
and metabolic instability. Here, we report the development of iP-selective
macrocyclic peptide epoxyketones prepared by a ring-closing metathesis
reaction between two terminal alkenes attached at the P2 and P3/P4
positions of linear counterparts. We show that a lead macrocyclic
compound DB-60 (20) effectively inhibits the catalytic
activity of iP in ABCB1-overexpressing cells (IC50: 105
nM) and has metabolic stability superior to its linear counterpart.
DB-60 (20) also lowered the serum levels of IL-1α
and ameliorated cognitive deficits in Tg2576 mice. The results collectively
suggest that macrocyclic peptide epoxyketones have improved CNS drug
properties than their linear counterparts and offer promising potential
as an AD drug candidate.

此前，我们曾报道，靶向免疫蛋白酶体（immunoproteasome, iP）的线性肽环氧酮，可在不依赖β淀粉样蛋白（amyloid β）的前提下，改善阿尔茨海默病（Alzheimer’s disease, AD）小鼠模型的认知功能。然而，这类化合物存在脑穿透性不佳、代谢稳定性不足等潜在问题，使其用于AD治疗的临床前景受限。
本研究中，我们报道了一类经闭环复分解反应（ring-closing metathesis reaction）制备的iP选择性大环肽环氧酮：该反应以线性对应物的P2与P3/P4位点所连接的两个末端烯烃为底物进行环合。
研究显示，先导大环化合物DB-60（20）可有效抑制过表达ABCB1细胞中iP的催化活性（半最大抑制浓度IC50：105 nM），且其代谢稳定性优于对应线性化合物。
DB-60（20）还可降低Tg2576小鼠血清中IL-1α的水平，并改善其认知缺陷。
综上，大环肽环氧酮相较其线性类似物，具备更优的中枢神经系统（Central Nervous System, CNS）药物成药性，有望成为阿尔茨海默病的候选治疗药物。