Syracuse

Structural characterization of the feline-immunodeficiency-virus envelope glycoprotein 36 ectodomain for the development of new antivirals.

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Desmaris, F. | Lemaire, D. | Ricard-Blum, S. | Chatrenet, B. | Forest, E.

Edité par CCSD ; Portland Press -

International audience. In the fight against the human HIV, new targets are being explored, such as the proteins involved in the process of fusion of the virus with the host cell. Recently, the first generation of fusion inhibitors (enfuvirtide), targeting gp41 (virus envelope glycoprotein 41), has become commercially available. However, this promising class of drugs has to be improved in respect of their efficacy and bioavailability. Considering the strong homologies between HIV and FIV (feline immunodeficiency virus), as well as the highly conserved structure of the transmembrane envelope protein among species, FIV represents a relevant model of pre-screening studies for HIV. Taking into account (i) sequence homologies between the ectodomain of HIV gp41 and FIV gp36 (envelope glycoprotein 36), (ii) structural data available for gp41 and (iii) the fact that synthetic peptides derived from gp36 are effective inhibitors of FIV infection, we designed several peptides derived from gp36 sequence. We checked that these peptides had the same structural features as the corresponding peptides from gp41 HIV by CD, analytical ultracentrifugation and 1H-2H (hydrogen-deuterium) exchange combined with MS. By combining this latter technique with surface-plasmon-resonance assays, we identified the amino acid residues of the C-terminal region of the ectodomain of gp36 that are critical for interaction with the N-terminal region. This gave clues for therapy and vaccines against FIV, thus providing helpful data for treatments against HIV.In the fight against the human HIV, new targets are being explored, such as the proteins involved in the process of fusion of the virus with the host cell. Recently, the first generation of fusion inhibitors (enfuvirtide), targeting gp41 (virus envelope glycoprotein 41), has become commercially available. However, this promising class of drugs has to be improved in respect of their efficacy and bioavailability. Considering the strong homologies between HIV and FIV (feline immunodeficiency virus), as well as the highly conserved structure of the transmembrane envelope protein among species, FIV represents a relevant model of pre-screening studies for HIV. Taking into account (i) sequence homologies between the ectodomain of HIV gp41 and FIV gp36 (envelope glycoprotein 36), (ii) structural data available for gp41 and (iii) the fact that synthetic peptides derived from gp36 are effective inhibitors of FIV infection, we designed several peptides derived from gp36 sequence. We checked that these peptides had the same structural features as the corresponding peptides from gp41 HIV by CD, analytical ultracentrifugation and 1H-2H (hydrogen-deuterium) exchange combined with MS. By combining this latter technique with surface-plasmon-resonance assays, we identified the amino acid residues of the C-terminal region of the ectodomain of gp36 that are critical for interaction with the N-terminal region. This gave clues for therapy and vaccines against FIV, thus providing helpful data for treatments against HIV.

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