Rebelo, MariaTang, CongCoelho, Ana R.Labão-Almeida, CarlosSchneider, Matthias M.Tatalick, LaurieRuivo, Pedrode Miranda, Marta PiresGomes, AndreiaCarvalho, TâniaWalker, Matthew J.Ausserwoeger, HannesSimas, J. PedroVeldhoen, MarcKnowles, Tuomas P. J.Silva, Daniel AdrianoShoultz, DavidBernardes, Gonçalo J. L.2023-10-042023-10-042023-09-150022-1899http://hdl.handle.net/10400.14/42778The emergence of novel variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) underscores the need to investigate alternative approaches to prevent infection and treat patients with coronavirus disease 2019. Here, we report the preclinical efficacy of NL-CVX1, a de novo decoy that blocks virus entry into cells by binding with nanomolar affinity and high specificity to the receptor-binding domain of the SARS-CoV-2 spike protein. Using a transgenic mouse model of SARS-CoV-2 infection, we showed that a single prophylactic intranasal dose of NL-CVX1 conferred complete protection from severe disease following SARS-CoV-2 infection. Multiple therapeutic administrations of NL-CVX1 also protected mice from succumbing to infection. Finally, we showed that infected mice treated with NL-CVX1 developed both anti-SARS-CoV-2 antibodies and memory T cells and were protected against reinfection a month after treatment. Overall, these observations suggest NL-CVX1 is a promising therapeutic candidate for preventing and treating severe SARS-CoV-2 infections.engCOVID-19De novo protein decoysK18-hACE2 miceSARS-CoV-2Treatmentjournal article85171601438PMC1050395137279654001002059700001