Scaffold Simplification Strategy Leads to a Novel Generation of Dual Human Immunodeficiency Virus and Enterovirus-A71 Entry Inhibitors.,Journal of Medicinal Chemistry

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Scaffold Simplification Strategy Leads to a Novel Generation of Dual Human Immunodeficiency Virus and Enterovirus-A71 Entry Inhibitors.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2019-12-20 , DOI: 10.1021/acs.jmedchem.9b01737
Belén Martínez-Gualda ₁ , Liang Sun ₂ , Olaia Martí-Marí ₁ , Sam Noppen ₂ , Rana Abdelnabi ₂ , Carol M Bator ₃ , Ernesto Quesada ₁ , Leen Delang ₂ , Carmen Mirabelli ₂ , Hyunwook Lee ₃ , Dominique Schols ₂ , Johan Neyts ₂ , Susan Hafenstein _{3,

4} , María-José Camarasa ₁ , Federico Gago ₅ , Ana San-Félix ₁

Affiliation

Currently, there are only three FDA-approved drugs that inhibit human immunodeficiency virus (HIV) entry-fusion into host cells. The situation is even worse for enterovirus EV71 infection for which no antiviral therapies are available. We describe here the discovery of potent entry dual inhibitors of HIV and EV71. These compounds contain in their structure three or four tryptophan (Trp) residues linked to a central scaffold. Critical for anti-HIV/EV71 activity is the presence of extra phenyl rings, bearing one or two carboxylates, at the C2 position of the indole ring of each Trp residue. The most potent derivatives, 22 and 30, inhibit early steps of the replicative cycles of HIV-1 and EV-A71 by interacting with their respective viral surfaces (glycoprotein gp120 of HIV and the fivefold axis of the EV-A71 capsid). The high potency, low toxicity, facile chemical synthesis, and great opportunities for chemical optimization make them useful prototypes for future medicinal chemistry studies.

中文翻译：

支架简化策略导致新一代的双重人类免疫缺陷病毒和肠病毒A71进入抑制剂。

当前，只有三种FDA批准的药物可以抑制人类免疫缺陷病毒（HIV）进入宿主细胞的融合。对于没有抗病毒治疗方法的肠病毒EV71感染，情况更糟。我们在这里描述了有效进入HIV和EV71双重抑制剂的发现。这些化合物在其结构中包含与中央支架相连的三个或四个色氨酸（Trp）残基。抗HIV / EV71活性的关键是在每个Trp残基的吲哚环的C2位上带有一个或两个羧酸盐的额外苯环的存在。最有效的衍生物22和30通过与它们各自的病毒表面（HIV的糖蛋白gp120和EV-A71衣壳的五倍轴）相互作用，抑制HIV-1和EV-A71的复制周期的早期步骤。高效，低毒，

更新日期：2019-12-20

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