Advanced Molecular Tweezers with Lipid Anchors against SARS-CoV-2 and Other Respiratory Viruses

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.

Automated summary

This study discovered that a class of drugs called molecular tweezers can disrupt the envelope of SARS-CoV-2 and render the virus non-infectious. By modifying the molecular structure, researchers identified a series of advanced molecular tweezers that showed enhanced ability to destroy lipid bilayers and suppress SARS-CoV-2 infection. These potentiated tweezers demonstrated activity against various viruses, including respiratory syncytial virus, influenza, and measles viruses, in addition to SARS-CoV-2. The inhibitory effects of the advanced tweezers against respiratory syncytial virus and SARS-CoV-2 were also validated in mice. Therefore, these broad-spectrum antiviral agents have great potential for clinical development in combating highly pathogenic viruses.