Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes the disease COVID-19 can lead to serious symptoms, such as severe pneumonia, in the elderly and those with underlying medical conditions. While vaccines are now available, they do not work for everyone and therapeutic drugs are still needed, particularly for treating life-threatening conditions. Here, we showed nasal delivery of a new, unmodified camelid single-domain antibody (VHH), termed K-874A, effectively inhibited SARS-CoV-2 titers in infected lungs of Syrian hamsters without causing weight loss and cytokine induction. In vitro studies demonstrated that K-874A neutralized SARS-CoV-2 in both VeroE6/TMPRSS2 and human lung-derived alveolar organoid cells. Unlike other drug candidates, K-874A blocks viral membrane fusion rather than viral attachment. Cryo-electron microscopy revealed K-874A bound between the receptor binding domain and N-terminal domain of the virus S protein. Further, infected cells treated with K-874A produced fewer virus progeny that were less infective. We propose that direct administration of K-874A to the lung could be a new treatment for preventing the reinfection of amplified virus in COVID-19 patients.
Highlights
Coronaviruses (CoV) are enveloped, single-stranded positive-sense RNA viruses
Betacoronaviruses are significant interest because they are responsible for the severe acute respiratory syndrome (SARS) and middle eastern respiratory syndrome (MERS) epidemics in the past and the coronavirus disease 2019 (COVID-19) pandemic
We used VHH-cDNA display for in vitro selection of VHHs against the SARS-CoV-2 S1 protein (Fig 1A). cDNA display yields functional VHHs, whose coding RNA is linked via a puromycin linker [13,14,15]
Summary
Coronaviruses (CoV) are enveloped, single-stranded positive-sense RNA viruses. They are divided into four genera: alpha, beta, gamma and delta. Betacoronaviruses are significant interest because they are responsible for the severe acute respiratory syndrome (SARS) and middle eastern respiratory syndrome (MERS) epidemics in the past and the coronavirus disease 2019 (COVID-19) pandemic These viruses can cause mild to severe respiratory tract infections and death in some cases. After binding to ACE2 via the RBD, a protease on the host cell surface cleaves and activates the S protein, allowing the virus membrane to fuse with the host cell membrane. Blocking this viral fusion is thought to be a promising therapeutic strategy [1,2]. Because SARS-CoV-2 infects cells in the nasal mucosa or lungs that express ACE2 [3], direct delivery of antiviral drugs to the respiratory system is expected to improve drug efficacy
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
