Novel Furin Inhibitors with Potent Anti-infectious Activity
Novel Furin Inhibitors with Potent Anti-infectious Activity
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DOI：
10.1002/cmdc.201500103
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发表时间：
2015-07-01
期刊：
影响因子：
3.4
通讯作者：
Steinmetzer, Torsten
中科院分区：
文献类型：
--
作者：
Hardes, Kornelia;Becker, Gero L.;Steinmetzer, Torsten
合成了P3位含有非天然氨基酸残基的新型仿肽呋喃类药物。最有效的化合物4-guanidinomethyl-phenylacteyl-Arg-Tle-Arg-4-amidinobenzylamide(MI-1148)抑制呋喃西林，K-I值为5.5pM衍生物对PC1/3也有很强的抑制作用，而对PC2的影响较小。选定的抑制剂在细胞培养中进行了抗菌和抗病毒活性测试，以对抗已知依赖于呋喃类活性的感染剂。在呋喃类抑制剂的存在下，观察到了对炭疽和白喉毒素的显著保护作用。此外，高致病性H5N1和H7N1禽流感病毒的传播和犬瘟病毒的繁殖得到了强有力的抑制。缓蚀剂MI-1148与人呋喃形成络合物结晶。它在P5苯环对位上的N-端胍甲基占据的位置与以前在间位上含有这种取代的结构相关抑制剂的位置相同，从而维持了所有重要的P5相互作用。我们的结果证实，抑制呋喃西林是一种有希望的短期治疗急性传染病的策略。
New peptidomimetic furin inhibitors with unnatural amino acid residues in the P3 position were synthesized. The most potent compound 4-guanidinomethyl-phenylacteyl-Arg-Tle-Arg-4-amidinobenzylamide (MI-1148) inhibits furin with a K-i value of 5.5pM. The derivatives also strongly inhibit PC1/3, whereas PC2 is less affected. Selected inhibitors were tested in cell culture for antibacterial and antiviral activity against infectious agents known to be dependent on furin activity. A significant protective effect against anthrax and diphtheria toxin was observed in the presence of the furin inhibitors. Furthermore, the spread of the highly pathogenic H5N1 and H7N1 avian influenza viruses and propagation of canine distemper virus was strongly inhibited. Inhibitor MI-1148 was crystallized in complex with human furin. Its N-terminal guanidinomethyl group in the para position of the P5 phenyl ring occupies the same position as that found previously for a structurally related inhibitor containing this substitution in the meta position, thereby maintaining all of the important P5 interactions. Our results confirm that the inhibition of furin is a promising strategy for a short-term treatment of acute infectious diseases.