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Article

Structure-Based Design of an RNase Chimera for Antimicrobial Therapy

by
Guillem Prats-Ejarque
1,*,
Helena Lorente
1,†,
Clara Villalba
1,†,
Raúl Anguita
1,
Lu Lu
1,2,
Sergi Vázquez-Monteagudo
1,
Pablo Fernández-Millán
1 and
Ester Boix
1,*
1
Department of Biochemistry and Molecular Biology, Faculty of Biosciences, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Spain
2
College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 625014, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2022, 23(1), 95; https://doi.org/10.3390/ijms23010095
Submission received: 18 November 2021 / Revised: 16 December 2021 / Accepted: 17 December 2021 / Published: 22 December 2021
(This article belongs to the Special Issue Exploring the Multifunctional Roles of Host Defence RNases under Stress Conditions)
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Abstract

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.
Keywords: RNase; protein engineering; structure-function relationship; antimicrobial proteins RNase; protein engineering; structure-function relationship; antimicrobial proteins
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MDPI and ACS Style

Prats-Ejarque, G.; Lorente, H.; Villalba, C.; Anguita, R.; Lu, L.; Vázquez-Monteagudo, S.; Fernández-Millán, P.; Boix, E. Structure-Based Design of an RNase Chimera for Antimicrobial Therapy. Int. J. Mol. Sci. 2022, 23, 95. https://doi.org/10.3390/ijms23010095

AMA Style

Prats-Ejarque G, Lorente H, Villalba C, Anguita R, Lu L, Vázquez-Monteagudo S, Fernández-Millán P, Boix E. Structure-Based Design of an RNase Chimera for Antimicrobial Therapy. International Journal of Molecular Sciences. 2022; 23(1):95. https://doi.org/10.3390/ijms23010095

Chicago/Turabian Style

Prats-Ejarque, Guillem, Helena Lorente, Clara Villalba, Raúl Anguita, Lu Lu, Sergi Vázquez-Monteagudo, Pablo Fernández-Millán, and Ester Boix. 2022. "Structure-Based Design of an RNase Chimera for Antimicrobial Therapy" International Journal of Molecular Sciences 23, no. 1: 95. https://doi.org/10.3390/ijms23010095

APA Style

Prats-Ejarque, G., Lorente, H., Villalba, C., Anguita, R., Lu, L., Vázquez-Monteagudo, S., Fernández-Millán, P., & Boix, E. (2022). Structure-Based Design of an RNase Chimera for Antimicrobial Therapy. International Journal of Molecular Sciences, 23(1), 95. https://doi.org/10.3390/ijms23010095

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