Supramolecular Mechanism of Viral Envelope Disruption by Molecular Tweezers

• DOI: 10.1021/jacs.0c06400
• Publication Date: 2020-09-14T22:19:17Z
• Authors: Tatjana Weil; Rüdiger Groß; Annika Röcker; Kenny Bravo-Rodri...; Christian Heid; Andrea Sowislok; My-Hue Le; Nelli Erwin; Mridula Dwivedi; Stephen M. Bart; Paul Bates; Lukas Wettstein; Janis A. Müller; Mirja Harms; Konstantin Sparrer; Yasser B. Ruiz-Bl...; Christina M. Stürzel; Jens von Einem; Sina Lippold; Clarissa Read; Paul Walther; Marco Hebel; Florian Kreppel; Frank-Gerrit Klärner; Gal Bitan; Michael Ehrmann; Tanja Weil; Roland Winter; Thomas Schrader; James Shorter; Elsa Sanchez-Garcia; Jan Münch
• Keywords: Viral membrane

Broad-spectrum antivirals are powerful weapons against dangerous viruses where no specific therapy exists, as in the case of ongoing SARS-CoV-2 pandemic. We discovered that a lysine- and arginine-specific supramolecular ligand (CLR01) destroys enveloped viruses, including HIV, Ebola, Zika virus, remodels amyloid fibrils semen promote viral infection. Yet, it is unknown how CLR01 exerts these two distinct therapeutic activities. Here, we delineate novel mechanism antiviral activity by studying tweezer variants: "phosphate tweezer" CLR01, "carboxylate CLR05, clip" PC. Lysine complexation inside cavity needed to antagonize amyloidogenesis only achieved CLR01. Importantly, CLR05 but not PC form closed inclusion complexes with lipid head groups membranes, thereby altering orientation increasing surface tension. This process disrupts envelopes diminishes infectivity leaves cellular membranes intact. Consequently, display broad all tested, herpesviruses, Measles influenza, SARS-CoV-2. Based on our mechanistic insights, potentiated antiviral, membrane-disrupting introducing aliphatic ester arms into each phosphate group act anchors membrane targeting. The most potent modifications harbored unbranched C4 units, which engendered tweezers were approximately one order magnitude more effective than nontoxic. Thus, establish basis envelope disruption new class potential broad-spectrum enhanced activity.