Advanced Molecular Tweezers with Lipid Anchors against SARS-CoV-2 and Other Respiratory Viruses
Tatjana Weil, Abbna Kirupakaran, My‐Hue Le, Philipp Rebmann, Joel Mieres‐Pérez, Leila Issmail, Carina Conzelmann, Janis A. Müller, Lena Rauch, Andrea Gilg, Lukas Wettstein, Rüdiger Groß, Clarissa Read, Tim Bergner, Sandra Pålsson, Nadja Uhlig, Valentina Eberlein, Heike Wöll, Frank‐Gerrit Klärner, Steffen Stenger, Beate M. Kümmerer, Hendrik Streeck, Giorgio Fois, Manfred Frick, Peter Braubach, Anna‐Lena Spetz, Thomas Grünwald, James Shorter, Elsa Sánchez‐García, Thomas Schräder, Jan Münch
Abstract
The COVID-19 pandemic caused by SARS-CoV-2 presents a global health emergency. Therapeutic options against SARS-CoV-2 are still very limited but urgently required. Molecular tweezers are supramolecular agents that destabilize the envelope of viruses resulting in a loss of viral infectivity. Here, we show that first-generation tweezers, CLR01 and CLR05, disrupt the SARS-CoV-2 envelope and abrogate viral infectivity. To increase the antiviral activity, a series of 34 advanced molecular tweezers were synthesized by insertion of aliphatic or aromatic ester groups on the phosphate moieties of the parent molecule CLR01. A structure-activity relationship study enabled the identification of tweezers with a markedly enhanced ability to destroy lipid bilayers and to suppress SARS-CoV-2 infection. Selected tweezer derivatives retain activity in airway mucus and inactivate the SARS-CoV-2 wildtype and variants of concern as well as respiratory syncytial, influenza, and measles viruses. Moreover, inhibitory activity of advanced tweezers against respiratory syncytial virus and SARS-CoV-2 was confirmed in mice. Thus, potentiated tweezers are broad-spectrum antiviral agents with great prospects for clinical development to combat highly pathogenic viruses.