Browsing by Author "Coelho, Ana R."
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- De novo human angiotensin - converting enzyme 2 Decoy NL-CVX1 protects mice from severe disease after severe acute respiratory syndrome coronavirus 2 infectionPublication . Rebelo, Maria; Tang, Cong; Coelho, Ana R.; Labão-Almeida, Carlos; Schneider, Matthias M.; Tatalick, Laurie; Ruivo, Pedro; de Miranda, Marta Pires; Gomes, Andreia; Carvalho, Tânia; Walker, Matthew J.; Ausserwoeger, Hannes; Simas, J. Pedro; Veldhoen, Marc; Knowles, Tuomas P. J.; Silva, Daniel Adriano; Shoultz, David; Bernardes, Gonçalo J. L.The 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.
- Proximity-Induced Nucleic Acid Degrader (PINAD) approach to targeted RNA degradation using small moleculesPublication . Mikutis, Sigitas; Rebelo, Maria; Yankova, Eliza; Gu, Muxin; Tang, Cong; Coelho, Ana R.; Yang, Mo; Hazemi, Madoka E.; Pires de Miranda, Marta; Eleftheriou, Maria; Robertson, Max; Vassiliou, George S.; Adams, David J.; Simas, J. Pedro; Corzana, Francisco; Schneekloth, John S.; Tzelepis, Konstantinos; Bernardes, Gonçalo J.L.Nature has evolved intricate machinery to target and degrade RNA, and some of these molecular mechanisms can be adapted for therapeutic use. Small interfering RNAs and RNase H-inducing oligonucleotides have yielded therapeutic agents against diseases that cannot be tackled using protein-centered approaches. Because these therapeutic agents are nucleic acid-based, they have several inherent drawbacks which include poor cellular uptake and stability. Here we report a new approach to target and degrade RNA using small molecules, proximity-induced nucleic acid degrader (PINAD). We have utilized this strategy to design two families of RNA degraders which target two different RNA structures within the genome of SARS-CoV-2: G-quadruplexes and the betacoronaviral pseudoknot. We demonstrate that these novel molecules degrade their targets using in vitro, in cellulo, and in vivo SARS-CoV-2 infection models. Our strategy allows any RNA binding small molecule to be converted into a degrader, empowering RNA binders that are not potent enough to exert a phenotypic effect on their own. PINAD raises the possibility of targeting and destroying any disease-related RNA species, which can greatly expand the space of druggable targets and diseases.