Division of Peptide Biochemistry, TUM School of Life Sciences, Technische Universität München, Emil-Erlenmeyer-Forum 5, 85354, Freising, Germany.
Current address: Life & Brain GmbH, Bonn, Germany.
Angew Chem Int Ed Engl. 2018 Oct 26;57(44):14503-14508. doi: 10.1002/anie.201802979. Epub 2018 Jul 24.
Amyloid self-assembly is linked to the pathogenesis of Alzheimer's disease (AD) and type 2 diabetes (T2D), but so far, no anti-amyloid compound has reached the clinic. Macrocyclic peptides belong to the most attractive drug candidates. Herein we present macrocyclic peptides (MCIPs) designed using minimal IAPP-derived recognition elements as a novel class of nanomolar amyloid inhibitors of both Aβ40(42) and IAPP or Aβ40(42) alone and show that chirality controls inhibitor selectivity. Sequence optimization led to the discovery of an Aβ40(42)-selective MCIP exhibiting high proteolytic stability in human plasma and human blood-brain barrier (BBB) crossing ability in a cell model, two highly desirable properties for anti-amyloid AD drugs. Owing to their favorable properties, MCIPs should serve as leads for macrocyclic peptide-based anti-amyloid drugs and scaffolds for the design of small-molecule peptidomimetics for targeting amyloidogenesis in AD or in both AD and T2D.
淀粉样蛋白自组装与阿尔茨海默病 (AD) 和 2 型糖尿病 (T2D) 的发病机制有关，但到目前为止，还没有一种抗淀粉样蛋白的化合物能进入临床。大环肽属于最有吸引力的药物候选物之一。本文介绍了使用最小的 IAPP 衍生识别元件设计的大环肽 (MCIPs)，作为一种新型的纳摩尔淀粉样蛋白抑制剂，可单独抑制 Aβ40(42)和 IAPP 或 Aβ40(42)，并表明手性控制抑制剂的选择性。通过序列优化，发现了一种 Aβ40(42)选择性的 MCIP，在人血浆中具有很高的蛋白酶稳定性，在细胞模型中具有穿过血脑屏障 (BBB) 的能力，这是抗淀粉样蛋白 AD 药物的两个非常理想的特性。由于其良好的性质，MCIP 应该作为基于大环肽的抗淀粉样蛋白药物的先导，以及设计针对 AD 或 AD 和 T2D 中淀粉样蛋白形成的小分子肽模拟物的支架。
