当前位置：
X-MOL 学术
›
J. Med. Chem.
›
论文详情
Our official English website, www.x-mol.net, welcomes your
feedback! (Note: you will need to create a separate account there.)
Engineering the Cyclization Loop of MCoTI-II Generates Targeted Cyclotides that Potently Inhibit Factor XIIa
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-11-16 , DOI: 10.1021/acs.jmedchem.2c01080 Sixin Tian 1 , Thomas Durek 1 , Conan K Wang 1 , Christina N Zdenek 2 , Bryan G Fry 2 , David J Craik 1 , Simon J de Veer 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-11-16 , DOI: 10.1021/acs.jmedchem.2c01080 Sixin Tian 1 , Thomas Durek 1 , Conan K Wang 1 , Christina N Zdenek 2 , Bryan G Fry 2 , David J Craik 1 , Simon J de Veer 1
Affiliation
|
Factor XIIa (FXIIa) is a promising target for developing new drugs that prevent thrombosis without causing bleeding complications. A native cyclotide (MCoTI-II) is gaining interest for engineering FXIIa-targeted anticoagulants as this peptide inhibits FXIIa but not other coagulation proteases. Here, we engineered the native biosynthetic cyclization loop of MCoTI-II (loop 6) to generate improved FXIIa inhibitors. Decreasing the loop length led to gains in potency up to 7.7-fold, with the most potent variant having five residues in loop 6 (Ki = 25 nM). We subsequently examined sequence changes within loop 6 and an adjacent loop, with substitutions at P4 and P2′ producing a potent FXIIa inhibitor (Ki = 2 nM) that displayed more than 700-fold selectivity, was stable in human serum, and blocked the intrinsic coagulation pathway in human plasma. These findings demonstrate that engineering the biosynthetic cyclization loop can generate improved cyclotide variants, expanding their potential for drug discovery.
中文翻译：
设计 MCoTI-II 的环化环可生成可有效抑制因子 XIIa 的靶向环肽
因子 XIIa (FXIIa) 是开发预防血栓形成而不引起出血并发症的新药的有前途的目标。天然环肽 (MCoTI-II) 越来越受到工程化 FXIIa 靶向抗凝血剂的兴趣，因为该肽抑制 FXIIa 但不抑制其他凝血蛋白酶。在这里，我们设计了 MCoTI-II 的天然生物合成环化环（环 6）以生成改进的 FXIIa 抑制剂。减少环长度导致效力增加高达 7.7 倍，最有效的变体在环 6 中有五个残基 ( K i = 25 nM)。我们随后检查了环 6 和相邻环内的序列变化，P4 和 P2' 处的替换产生了一种有效的 FXIIa 抑制剂 ( K i= 2 nM)，显示出超过 700 倍的选择性，在人血清中稳定，并阻断人血浆中的内在凝血途径。这些发现表明，对生物合成环化环进行工程改造可以产生改进的环肽变体，从而扩大其药物发现的潜力。
更新日期：2022-11-16
中文翻译：
设计 MCoTI-II 的环化环可生成可有效抑制因子 XIIa 的靶向环肽
因子 XIIa (FXIIa) 是开发预防血栓形成而不引起出血并发症的新药的有前途的目标。天然环肽 (MCoTI-II) 越来越受到工程化 FXIIa 靶向抗凝血剂的兴趣，因为该肽抑制 FXIIa 但不抑制其他凝血蛋白酶。在这里，我们设计了 MCoTI-II 的天然生物合成环化环（环 6）以生成改进的 FXIIa 抑制剂。减少环长度导致效力增加高达 7.7 倍，最有效的变体在环 6 中有五个残基 ( K i = 25 nM)。我们随后检查了环 6 和相邻环内的序列变化，P4 和 P2' 处的替换产生了一种有效的 FXIIa 抑制剂 ( K i= 2 nM)，显示出超过 700 倍的选择性，在人血清中稳定，并阻断人血浆中的内在凝血途径。这些发现表明，对生物合成环化环进行工程改造可以产生改进的环肽变体，从而扩大其药物发现的潜力。
京公网安备 11010802027423号