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Supramolecular Mechanism of Viral Envelope Disruption by Molecular Tweezers.
Weil, Tatjana; Groß, Rüdiger; Röcker, Annika; Bravo-Rodriguez, Kenny; Heid, Christian; Sowislok, Andrea; Le, My-Hue; Erwin, Nelli; Dwivedi, Mridula; Bart, Stephen M; Bates, Paul; Wettstein, Lukas; Müller, Janis A; Harms, Mirja; Sparrer, Konstantin; Ruiz-Blanco, Yasser B; Stürzel, Christina M; von Einem, Jens; Lippold, Sina; Read, Clarissa; Walther, Paul; Hebel, Marco; Kreppel, Florian; Klärner, Frank-Gerrit; Bitan, Gal; Ehrmann, Michael; Weil, Tanja; Winter, Roland; Schrader, Thomas; Shorter, James; Sanchez-Garcia, Elsa; Münch, Jan.
  • Weil T; Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany.
  • Groß R; Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany.
  • Röcker A; Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany.
  • Bravo-Rodriguez K; Computational Biochemistry, Center of Medical Biotechnology, University of Duisburg-Essen, 45117 Essen, Germany.
  • Heid C; Faculty of Chemistry, University of Duisburg-Essen, 45117 Essen, Germany.
  • Sowislok A; Faculty of Chemistry, University of Duisburg-Essen, 45117 Essen, Germany.
  • Le MH; Faculty of Chemistry, University of Duisburg-Essen, 45117 Essen, Germany.
  • Erwin N; Physical Chemistry I-Biophysical Chemistry, Faculty of Chemistry and Chemical Biology, TU Dortmund University, 44227 Dortmund, Germany.
  • Dwivedi M; Physical Chemistry I-Biophysical Chemistry, Faculty of Chemistry and Chemical Biology, TU Dortmund University, 44227 Dortmund, Germany.
  • Bart SM; Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
  • Bates P; Cell and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
  • Wettstein L; Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
  • Müller JA; Cell and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
  • Harms M; Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany.
  • Sparrer K; Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany.
  • Ruiz-Blanco YB; Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany.
  • Stürzel CM; Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany.
  • von Einem J; Computational Biochemistry, Center of Medical Biotechnology, University of Duisburg-Essen, 45117 Essen, Germany.
  • Lippold S; Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany.
  • Read C; Institute of Virology, Ulm University Medical Center, 89081 Ulm, Germany.
  • Walther P; Institute of Virology, Ulm University Medical Center, 89081 Ulm, Germany.
  • Hebel M; Institute of Virology, Ulm University Medical Center, 89081 Ulm, Germany.
  • Kreppel F; Central Facility for Electron Microscopy, Ulm University, 89081 Ulm, Germany.
  • Klärner FG; Central Facility for Electron Microscopy, Ulm University, 89081 Ulm, Germany.
  • Bitan G; Max Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany.
  • Ehrmann M; Institute of Inorganic Chemistry I, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
  • Weil T; Center for Biomedical Education and Research, University of Witten/Herdecke, Stockumer Strasse 10, 58453 Witten, Germany.
  • Winter R; Faculty of Chemistry, University of Duisburg-Essen, 45117 Essen, Germany.
  • Schrader T; Department of Neurology, David Geffen School of Medicine, Brain Research Institute, and Molecular Biology Institute, University of California, Los Angeles, Los Angeles, California 90095, United States.
  • Shorter J; Microbiology II, Center of Medical Biotechnology, University of Duisburg-Essen, 45117 Essen, Germany.
  • Sanchez-Garcia E; Max Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany.
  • Münch J; Institute of Inorganic Chemistry I, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
J Am Chem Soc ; 142(40): 17024-17038, 2020 10 07.
Article in English | MEDLINE | ID: covidwho-772998
Semantic information from SemMedBD (by NLM)
1. Plant seeds LOCATION_OF Amyloid Fibrils
Subject
Plant seeds
Predicate
LOCATION_OF
Object
Amyloid Fibrils
2. Amyloid Fibrils PREDISPOSES Virus Diseases
Subject
Amyloid Fibrils
Predicate
PREDISPOSES
Object
Virus Diseases
3. Head LOCATION_OF Lipid panel
Subject
Head
Predicate
LOCATION_OF
Object
Lipid panel
4. Plant seeds LOCATION_OF Amyloid Fibrils
Subject
Plant seeds
Predicate
LOCATION_OF
Object
Amyloid Fibrils
5. Amyloid Fibrils PREDISPOSES Virus Diseases
Subject
Amyloid Fibrils
Predicate
PREDISPOSES
Object
Virus Diseases
6. Head LOCATION_OF Lipid panel
Subject
Head
Predicate
LOCATION_OF
Object
Lipid panel
ABSTRACT
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.
Subject(s)

Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Organophosphates / Bridged-Ring Compounds / Viral Envelope Proteins Type of study: Experimental Studies / Randomized controlled trials Topics: Variants Limits: Humans Language: English Journal: J Am Chem Soc Year: 2020 Document Type: Article Affiliation country: Jacs.0c06400

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Organophosphates / Bridged-Ring Compounds / Viral Envelope Proteins Type of study: Experimental Studies / Randomized controlled trials Topics: Variants Limits: Humans Language: English Journal: J Am Chem Soc Year: 2020 Document Type: Article Affiliation country: Jacs.0c06400