Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Department of Chemistry, Faculty of Exact Sciences, Bar-Ilan University, Ramat Gan, 5290002, Israel.
Eur J Med Chem. 2022 Jan 15;228:113969. doi: 10.1016/j.ejmech.2021.113969. Epub 2021 Nov 3.
Human α1-antitrypsin (hAAT) has two distinguishing functions: anti-protease activity and regulation of the immune system. In the present study we hypothesized that those two protein functions are mediated by different structural domains on the hAAT surface. Indeed, such biologically active immunoregulatory sites (not associated with canonical anti-protease activity) on the surface of hAAT were identified by in silico methods. Several peptides were derived from those immunoregulatory sites. Four peptides exhibited impressive biological effects in pharmacological concentration ranges. Peptidomimetic (14) was developed, based on the structure of the most druggable and active peptide. The compound exhibited a potent anti-inflammatory activity in vitro and in vivo. Such a compound could be used as a basis for developing novel anti-inflammatory drug candidates and as a research tool for better understanding hAAT functions.
人α1-抗胰蛋白酶（hAAT）具有两种独特的功能：抗蛋白酶活性和免疫系统调节。在本研究中，我们假设这两种蛋白质功能是由 hAAT 表面上不同的结构域介导的。实际上，通过计算机模拟方法确定了 hAAT 表面上存在的具有生物活性的免疫调节位点（与经典抗蛋白酶活性无关）。从这些免疫调节位点衍生出了几种肽。其中四种肽在药理学浓度范围内表现出显著的生物学效应。基于最具成药性和活性的肽的结构，开发了肽模拟物（14）。该化合物在体外和体内均表现出强大的抗炎活性。这种化合物可用作开发新型抗炎药物候选物的基础，并作为更好地了解 hAAT 功能的研究工具。
