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Página principal > Artículos > Artículos publicados > Structure-Based Design of an RNase Chimera for Antimicrobial Therapy |
Fecha: | 2022 |
Resumen: | Bacterial resistance to antibiotics urges the development of alternative therapies. Based on the structure-function of antimicrobial members of the RNase A superfamily, we have developed a hybrid enzyme. Within this family, RNase 1 exhibits the highest catalytic activity and the lowest cytotoxicity; in contrast, RNase 3 shows the highest bactericidal action, alas with a reduced catalytic activity. Starting from both parental proteins, we designed a first RNase 3/1-v1 chimera. The construct had a catalytic activity much higher than RNase 3, unfortunately without reaching an equivalent antimicrobial activity. Thus, two new versions were created with improved antimicrobial properties. Both of these versions (RNase 3/1-v2 and -v3) incorporated an antimicrobial loop characteristic of RNase 3, while a flexible RNase 1-specific loop was removed in the latest construct. RNase 3/1-v3 acquired both higher antimicrobial and catalytic activities than previous versions, while retaining the structural determinants for interaction with the RNase inhibitor and displaying non-significant cytotoxicity. Following, we tested the constructs' ability to eradicate macrophage intracellular infection and observed an enhanced ability in both RNase 3/1-v2 and v3. Interestingly, the inhibition of intracellular infection correlates with the variants' capacity to induce autophagy. We propose RNase 3/1-v3 chimera as a promising lead for applied therapeutics. |
Ayudas: | Agència de Gestió d'Ajuts Universitaris i de Recerca 2016/PROD00060 Agència de Gestió d'Ajuts Universitaris i de Recerca 2019/LLAV00002 Ministerio de Economía y Competitividad SAF2015-66007P Agencia Estatal de Investigación PID2019-106123GB-I00 |
Nota: | Altres ajuts: Fundació La Marató de TV3/TV3-201803-10 |
Derechos: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. |
Lengua: | Anglès |
Documento: | Article ; recerca ; Versió publicada |
Materia: | RNase ; Protein engineering ; Structure-function relationship ; Antimicrobial proteins |
Publicado en: | International journal of molecular sciences, Vol. 23, Issue 1 (January 2022) , art. 95, ISSN 1422-0067 |
21 p, 25.6 MB |