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web del Instituto de Biología Molecular y Celular

Group name: ENVELOPED VIRUSES. BIOMEMBRANES, PROTEINS AND DESIGN ON NOVEL ANTIVIRALS


Among the pathogens which cause the higher rates of mortality and morbidity on humans and animals we can name the viruses. However, in the vast majority of cases, there are no vaccines or effective therapeutic treatments. Flaviviridae constitute a large family of viruses to which medically highly relevant human pathogens belong. Viruses such as the hepatitis C virus, the Yellow Fever Virus, West Nile virus, Tick-Borne Encephalitis Viruses, Zika and Dengue belong to this family. Dengue (DENV), as well as Zika (ZIKV), cause the most prevalent arthropod-borne viral disease among humans affecting millions of people per year. These diseases have evolved from a sporadic occurrence to a global public health problem. The number of reported cases is increasing geometrically due to environmental and geographical changes and many countries, including ours, have a direct risk to them. Significantly, all processes inherent to the viral replication cycle are directly or indirectly related to membrane systems or membranes derived from them. Anything that might interfere with any one of these processes would be potentially useful in ensuring that the virus cannot get in or out of the cell. Our group aims to study the structure and interaction with different types of model biomembrane systems of several peptide domains derived from the structural and non-structural proteins of DENV and ZIKV viruses. Our goal will be to distinguish and correlate the effects on both the peptides and the membrane components, with the specific aims of obtaining, on the one hand, the knowledge of the molecular mechanism of the biological function of the original proteins and on the other, effective antiviral and bioactive molecules against them. Relaying on the knowledge we have about the structural and non-structural proteins of DENV, our experimental approach and objectives will consist of using in silico molecular dynamics to find the specific interacting three dimensional structure of selected peptides of DENV and ZIKV with biomembrane model systems, in vitro obtain exhaustive information about its structure and specific lipid interaction, in silico screening and peptide docking methodologies to obtain antiviral peptides and bioactive molecules against those obtained structure, and test them to check their effectivity using different model biomembrane compositions. These data will permit us the development of new leading compounds useful for improved combined therapies in order to achieve the ultimate goal, eradicate the DENV and ZIKV viral infections.

RESEARCH HIGHLIGHTS

J Biomol Struct Dyn. 2016 Apr 21:1-41. PMID: 27098294. Molecular Dynamics Study of the Membrane Interaction of a Membranotropic Dengue Virus C Protein Derived Peptide. Fajardo-Sánchez E, Galiano V, Villalaín J.

Dengue virus C protein, essential in the Dengue virus life cycle, possess a segment, peptide PepC, known to bind membranes. To characterize its interaction with the membrane we have used the molecular dynamics HMMM membrane model system. This approach is able of achieving a stable system and sampling the peptide/lipid interactions which determine the orientation and insertion of the peptide upon membrane binding. We have been able of demonstrating spontaneous binding of PepC to the DVPC/DVPA membrane model system whereas no binding was observed at all for the DVPC. PepC, adopting an -helix profile, did not insert into the membrane but did bind to its surface through a charge anchor formed by its three positively-charged residues. The positively-charged amino acids residues Arg-2, Lys-6 and Arg-16 are the main responsible for the peptide binding to the membrane stabilizing the structure of the bound peptide. These data should help in our understanding of the molecular mechanism of DENV life cycle as well as making possible the future development of potent inhibitor molecules, which target Dengue virus C protein structures involved in membrane binding.

Membr Biol. 2016 Feb 3. PMID: 26843065. The Location of the Protonated and Unprotonated Forms of Arbidol in the Membrane: A Molecular Dynamics Study. Galiano V, Villalaín J.

Arbidol is a potent broad-spectrum antiviral molecule for the treatment and prophylaxis of many viral infections but no information is available of the molecular basis of its antiviral mechanism/s. Arbidol incorporates rapidly into biological membranes and some of its antiviral effects might be related to its capacity to interact with and locate into the membrane. We have aimed to locate the protonated (Arp) and un-protonated (Arb) forms of arbidol in a model membrane system. Whereas both Arb and Arp average location in the membrane palisade is a similar one, Arb tends to be perpendicular to the membrane surface whereas Arp tends to be parallel to it. Furthermore, Arp, in contrast to Arb, seems to interact stronger with POPG than with POPC, implying the existence of a specific interaction between Arp, the protonated from, with negatively-charged phospholipids. This data would suggest that the active molecule of arbidol in the membrane is the protonated one, i.e., the positively charged molecule. The broad antiviral activity of arbidol would be defined by the perturbation it exerts on membrane structure and therefore membrane functioning.


STAFF

José Villalaín Boullón

Vicente Galiano Ibarra

POSTDOCTORAL FELLOWS

Emmanuel Fajardo Sanchez

PUBLICATIONS (ARTICLES)

  1. J Biomol Struct Dyn. 2016 Apr 21:1-41. PMID: 27098294. Molecular Dynamics Study of the Membrane Interaction of a Membranotropic Dengue Virus C Protein Derived Peptide. Fajardo-Sánchez E, Galiano V, Villalaín J.
  2. J Membr Biol. 2016 Feb 3. PMID: 26843065. The Location of the Protonated and Unprotonated Forms of Arbidol in the Membrane: A Molecular Dynamics Study. Galiano V, Villalaín J.
  3. Biochim Biophys Acta. 2015 Nov;1848(11 Pt A):2849-58. doi: 10.1016/j.bbamem.2015.08.007. Oleuropein aglycone in lipid bilayer membranes. A molecular dynamics study. Galiano V, Villalaín J.
  4. J Phys Chem B. 2014 Aug 28;118(34):10142-55. doi: 10.1021/jp504911r. Membrane interacting regions of Dengue virus NS2A protein. Nemésio H, Villalaín J.
  5. Biochemistry. 2014 Aug 19;53(32):5280-9. doi: 10.1021/bi500724k. Membranotropic regions of the dengue virus prM protein. Nemésio H, Villalaín J.
  6. Mol Membr Biol. 2013 Jul;30(4):273-87. doi: 10.3109/09687688.2013.805835. Hydrophobic segment of dengue virus C protein. Interaction with model membranes. Nemésio H, Palomares-Jerez MF, Villalaín J.
  7. Biochim Biophys Acta. 2013 Aug;1828(8):1938-52. doi: 10.1016/j.bbamem.2013.04.020. N-terminal AH2 segment of protein NS4B from hepatitis C virus. Binding to and interaction with model biomembranes. Palomares-Jerez MF, Nemesio H, Franquelim HG, Castanho MA, Villalaín J.