Virus engineering and Nanobiotechnology
Research summary:
Major research goals: We use protein engineering techniques and biochemical, biophysical and virological analyses to study assembly, conformational stability and dynamics and physical properties of viruses, and their biological relevance (Mateu (ed.) (2013) Structure and Physics of Viruses, Springer 2013; Mateu (2013) Arch.Biochem.Biophys. 531,65-79). Based on these studies, we aim also at the design and analysis of genetically and/or structurally modified viral particles for the development of biomedical and bionanotechnological applications (Mateu (2016). In Protein-based Engineered Nanostructures, Springer 2016, pp.83-120).
Scientific relevance and technological implications: In-depth knowledge of certain key processes for viral infection, including virus morphogenesis, structural rearrangements and uncoating; application of this knowledge for the design of vaccines, antiviral drugs, biomaterials and modified nanoparticles for biomedical or bionanotechnological uses.
Some recent results: i) The combined use of atomic force microscopy (AFM) and electron microscopy allowed us to experimentally determine for the first time the reversible pathway and intermediates of assembly and disassembly of a structurally simple spherical virus (Fig.1). ii) Using mutational analysis and the determination of mechanical properties of virus particles by AFM we have discovered a relationship between genetic changes that alter the mechanical stiffness of virus particles and changes in the propensity of the latter to undergo conformational changes related to the infection process (Fig.2). iii) we have characterized the structure, dynamics and mechanical properties of a bidimensional nanocoating made by self-assembly of the HIV capsid protein on a solid matrix. These and other studies by our group have implications for a better understanding of processes essential for viral infection, the design of new antivirals that may inhibit these processes, and the development of nanoparticles and bidimensional biomaterials with improved mechanical properties for applications such as targeted drug delivery or tissue regeneration.
Fig. 1: Intermediates during the reversible assembly-disassembly pathway of the minute virus of mice capsid. Assembly proceeds through formation of a nucleus and the gradual association of capsid building blocks formed by trimers of the capsid protein.
Fig. 2: Linear relationship between an increase in mechanical stiffness of the minute virus of mice mediated by capsid-nucleic acid interactions, and an increase in its resistance against loss of infectivity by a heat-induced conformational change. This virus appears to have evolved genome binding sites in the capsid inner wall, which increases its stiffness and, in consequence, its resistance against thermal inactivation in the extracellular medium.
| Last name | Name | Laboratory | Ext.* | Professional category | |
|---|---|---|---|---|---|
| Escrig Traver | Judith | 205 | 4601 | jescrig(at)cbm.csic.es | Contrato Predoctoral |
| García Mateu | Mauricio | 205 | 4575 | mgarcia(at)cbm.csic.es | Catedrático Universidad, GA |
| Gil Redondo | Juan Carlos | 205 | 4601 | jcgil(at)cbm.csic.es | Investigador |
| Valbuena Jiménez | Alejandro | 205 | 4601 | avalbuena(at)cbm.csic.es | Profesor Ayudante Doctor |
| Valiente Martínez Sicluna | Luis | 205 | 4601 | luis.valiente(at)cbm.csic.es | Contrato Predoctoral |
Relevant publications:
- Mateo, R., Luna, E., Rincón, V. and Mateu, M.G. (2008). Engineering viable foot-and-mouth disease virus of increased stability as a step in the development of improved vaccines. J.Virol. 82, 12232-12240.
- Carrasco, C., Castellanos, M., de Pablo, P.J. and Mateu, M.G. (2008). Manipulation of the mechanical properties of a virus by protein engineering. Proc. Natl. Acad. Sci. USA 105, 4150-4155.
- Bocanegra, R., Domenech, R., Nevot, M., Rodriguez-Huete, A., López, I., Fuertes, M.A., Cavasotto, C., Martínez, M.A., Neira, J.L. and Mateu, M.G. (2011). Rationally designed interfacial peptides are efficient in vitro inhibitors of HIV-1 capsid assembly with antiviral activity. PLoS ONE. 6, e23877.
- Castellanos, M., Pérez, R., Carrasco, C., Hernando-Pérez, M., Gómez-Herrero, J., de Pablo, P.J. and Mateu, M.G. (2012). A balance between stiffness and elasticity provides a mechanical foundation for the infectivity of a virus. Proc. Natl. Acad. Sci. USA 109, 12028-12033.
- Rincón, V., Rodriguez-Huete, A., López-Argüello, S., Ibarra-Molero, B., Sánchez-Ruiz, J.M., Harmsen, M.M. and Mateu, M.G. (2014). Identification of the structural basis of thermal lability of a virus provides a rationale for improved vaccines. Structure 22, 1560-1570.
- Castellanos, M., Carrillo, P.J.P. and Mateu, M.G. (2015). Quantitatively probing propensity for structural transitions in engineered virus nanoparticles by single molecule mechanical analysis. Nanoscale 7, 5654-5664.
- Valbuena, A. and Mateu, M.G. (2015). Quantification and modification of the equlibrium dynamics and mechanics of a virus capsid lattice self-assembled as a protein nanocoating. Nanoscale 7, 14953-14964.
- Medrano, M., Fuertes, M.A., Valbuena, A., Carrillo, P.J.P., Rodríguez-Huete, A. and Mateu, M.G. (2016). Imaging and quantitation of a succession of transient intermediates reveal the self-assembly pathway of a simle icosahedral virus capsid. J. Am. Chem. Soc. 138, 15385-15396.
- Carrillo, P.J.P., Medrano, M., Valbuena, A., Rodríguez-Huete, A., Castellanos, M., Pérez, R. and Mateu, M.G. (2017). Amino acid side chains buried along intersubunit interfaces in a viral capsid preserve low mechanical stiffness associated with virus infectivity. ACS Nano 11, 2194-2208.
- Valbuena, A., Rodríguez-Huete, A. and Mateu, M.G. (2018). Mechanical stiffening of human rhinovirus by cavity-fiilling antiviral drugs. Nanoscale 10, 1440-1452.
Doctoral theses:
- Milagros Castellanos Molina (2011). Análisis mutacional de propiedades estructurales y mecánicas del virus diminuto del ratón, y de sus implicaciones biológicas. Universidad Autónoma de Madrid. Director: Mauricio G. Mateu.
- Rebeca Bocanegra Rojo (2011). Ensamblaje in vitro de la cápsida del virus de la inmunodeficiencia humana, y su inhibición por péptidos diseñados racionalmente. Universidad Autónoma de Madrid. Director: Mauricio G. Mateu.
- Verónica Rincón Forero (2012). Relaciones estructura-función en la cápsida del virus de la fiebre aftosa: algunas implicaciones para el desarrollo de vacunas y antivirales. Universidad Autónoma de Madrid. Director: Mauricio G. Mateu.
- Pablo Pérez Carrillo (2015). Papel de Interfases y residuos interfásicos en la elasticidad mecánica y dinámica conformacional de partículas del virus diminuto del ratón. Universidad Autónoma de Madrid. Director: Mauricio G. Mateu.
- María Medrano García (2018). Fundamentos moleculares del ensamblaje y las propiedades mecánicas de partículas víricas con aplicaciones biotecnológicas y nanotecnológicas. Universidad Autónoma de Madrid. Director: Mauricio G. Mateu.
- Silvia Daiana López Argüello (2019). Relaciones entre estructura, ensamblaje, estabilidad e infectividad de picornavirus. Universidad Autónoma de Madrid. Directores: Mauricio G. Mateu y Alejandro Valbuena.
