Supramolecular Mechanism of Viral Envelope Disruption by Molecular Tweezers.
Supramolecular Mechanism of Viral Envelope Disruption by Molecular Tweezers.
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DOI：
10.1021/jacs.0c06400
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发表时间：
2020-10-07
影响因子：
15
通讯作者：
Münch J
中科院分区：
文献类型：
--
作者：
Weil T;Groß R;Röcker A;Bravo-Rodriguez K;Heid C;Sowislok A;Le MH;Erwin N;Dwivedi M;Bart SM;Bates P;Wettstein L;Müller JA;Harms M;Sparrer K;Ruiz-Blanco YB;Stürzel CM;von Einem J;Lippold S;Read C;Walther P;Hebel M;Kreppel F;Klärner FG;Bitan G;Ehrmann M;Weil T;Winter R;Schrader T;Shorter J;Sanchez-Garcia E;Münch J
广谱抗病毒药物是对付危险病毒的强大武器，在没有特定疗法的情况下，如正在进行的SARS-CoV-2大流行。我们发现赖氨酸和精氨酸特异性超分子配体（CLR 01）破坏包膜病毒，包括HIV，埃博拉病毒和寨卡病毒，并重塑精液中促进病毒感染的淀粉样纤维。然而，目前尚不清楚CLR 01如何发挥这两种不同的治疗活性。在这里，我们描绘了一个新的抗病毒活性的机制，通过研究镊子变体的活性：“磷酸镊子”CLR 01，“羧酸镊子”CLR 05，和“磷酸夹”PC。需要镊子腔内的赖氨酸络合来拮抗淀粉样蛋白生成，并且仅通过CLR 01实现。重要的是，CLR 01和CLR 05而不是PC与病毒膜的脂质头部基团形成封闭的包合复合物，从而改变脂质取向并增加表面张力。这一过程破坏了病毒包膜，降低了感染性，但使细胞膜保持完整。因此，CLR 01和CLR 05对所有测试的包膜病毒显示出广泛的抗病毒活性，包括疱疹病毒、麻疹病毒、流感病毒和SARS-CoV-2。基于我们的机理见解，我们通过将脂肪族酯臂引入每个磷酸基团中以充当促进膜靶向的脂质锚来增强CLR 01的抗病毒、膜破坏活性。最有效的酯修饰含有未支化的C4单元，其产生的镊子比CLR 01有效约一个数量级并且无毒。因此，我们建立了通过特定镊子破坏病毒包膜的机制基础，并建立了一类新的具有增强活性的潜在广谱抗病毒药物。
Broad-spectrum antivirals are powerful weapons against dangerous viruses where no specific therapy exists, as in the case of the ongoing SARS-CoV-2 pandemic. We discovered that a lysine- and arginine-specific supramolecular ligand (CLR01) destroys enveloped viruses, including HIV, Ebola, and Zika virus, and remodels amyloid fibrils in semen that promote viral infection. Yet, it is unknown how CLR01 exerts these two distinct therapeutic activities. Here, we delineate a novel mechanism of antiviral activity by studying the activity of tweezer variants: the “phosphate tweezer” CLR01, a “carboxylate tweezer” CLR05, and a “phosphate clip” PC. Lysine complexation inside the tweezer cavity is needed to antagonize amyloidogenesis and is only achieved by CLR01. Importantly, CLR01 and CLR05 but not PC form closed inclusion complexes with lipid head groups of viral membranes, thereby altering lipid orientation and increasing surface tension. This process disrupts viral envelopes and diminishes infectivity but leaves cellular membranes intact. Consequently, CLR01 and CLR05 display broad antiviral activity against all enveloped viruses tested, including herpesviruses, Measles virus, influenza, and SARS-CoV-2. Based on our mechanistic insights, we potentiated the antiviral, membrane-disrupting activity of CLR01 by introducing aliphatic ester arms into each phosphate group to act as lipid anchors that promote membrane targeting. The most potent ester modifications harbored unbranched C4 units, which engendered tweezers that were approximately one order of magnitude more effective than CLR01 and nontoxic. Thus, we establish the mechanistic basis of viral envelope disruption by specific tweezers and establish a new class of potential broad-spectrum antivirals with enhanced activity.
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包膜病毒的肽进入抑制剂：界面疏水性的重要性。
DOI：
10.1016/j.bbamem.2014.04.015
发表时间：
2014-09
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
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通讯作者：
Wimley WC
影响因子：
3.3
作者：
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通讯作者：
Münch J
影响因子：
2.9
作者：
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通讯作者：
Makhatadze GI
影响因子：
4.2
作者：
Castellano LM;Shorter J
通讯作者：
Shorter J
影响因子：
7.8
作者：
Liao, Maofu;Kielian, Margaret
通讯作者：
Kielian, Margaret