Supramolecular Mechanism of Viral Envelope Disruption by Molecular Tweezers
| العنوان: | Supramolecular Mechanism of Viral Envelope Disruption by Molecular Tweezers |
|---|---|
| المؤلفون: | Florian Kreppel, Janis A. Müller, Jens von Einem, Tatjana Weil, Elsa Sanchez-Garcia, Clarissa Read, Sina Lippold, Gal Bitan, Christina M. Stürzel, Thomas Schrader, Michael Ehrmann, Marco Hebel, Frank-Gerrit Klärner, Roland Winter, Paul Bates, Mridula Dwivedi, Andrea Sowislok, Tanja Weil, Annika Röcker, Jan Münch, Rüdiger Groß, Konstantin M. J. Sparrer, Lukas Wettstein, Yasser B. Ruiz-Blanco, Paul Walther, Kenny Bravo-Rodriguez, My Hue Le, James Shorter, Nelli Erwin, Mirja Harms, Stephen M. Bart, Christian Heid |
| المصدر: | Journal of the American Chemical Society, vol 142, iss 40 Journal of the American Chemical Society |
| بيانات النشر: | eScholarship, University of California, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Bridged-Ring Compounds, Amyloid, Magnetic Resonance Spectroscopy, Anti-HIV Agents, viruses, Acid Phosphatase, Lysine, Chemie, HIV Infections, Arginine, Seminal Vesicle Secretory Proteins, 010402 general chemistry, Antiviral Agents, 01 natural sciences, Biochemistry, Article, Catalysis, Measles virus, Betacoronavirus, Structure-Activity Relationship, Colloid and Surface Chemistry, Viral Envelope Proteins, Viral envelope, Humans, Structure–activity relationship, Infectivity, biology, SARS-CoV-2, Chemistry, Cell Membrane, Zika Virus, General Chemistry, Ligand (biochemistry), biology.organism_classification, Lipids, Organophosphates, 0104 chemical sciences, 3. Good health, Cell biology, Membrane, Chemical Sciences, HIV-1, Biologie, Molecular tweezers |
| الوصف: | 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. |
| وصف الملف: | application/pdf |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::946cf9bab288e137126d44b6bb9cf2e0Test https://escholarship.org/uc/item/3049q3fvTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....946cf9bab288e137126d44b6bb9cf2e0 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |