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Viruses are small intracellular parasites that must invade a living cell to reproduce. There are very few effective antiviral drugs and just for some viral infections. In recent years, some research groups demonstrated the ability of 25-hydroxycholesterol (25HC) to inhibit the replication of several viruses, including human immunodeficiency virus (HIV), hepatitis C virus (HCV) and Zika virus (ZIKV). It has already been shown that this sterol blocks the viral fusion, but the mechanism behind its action has not been clarified. Thus, the first objective of my Ph.D. Thesis was to understand the effects of cholesterol replacement by 25HC at the membrane level, in the process of membrane fusion, as well as the effect of this membrane alterations on the secondary structure of the HIV fusion peptide. We found that the presence of 25HC deeply modifies the biophysical properties of membranes, promoting changes in membrane fluidity and order and altering its dipole potential. Moreover, we demonstrated that 25HC has also an effect on HIV fusion peptide structure. Despite the enlightening results, the use of 25HC as an antiviral therapy has some limitations. With this in mind, our proposal was to study fusion inhibitor peptides conjugated to 25-hydroxycholesterol, turning the sterol more specific towards the target. Additionally, the conjugation of a lipid moiety, with antiviral activity, to fusion inhibitor peptides should improve their pharmacokinetic and pharmacodynamic properties and turn the peptide less prone to mutations. Therefore, we characterized the interaction of two antiviral peptides (against human immunodeficiency virus and measles virus), both conjugated to 25HC, with biomembranes model systems and peripheral blood cells. Overall, in this Thesis are presented several results that contribute to a better knowledge of the mechanisms associated with the antiviral functions of 25HC. In addition, a new strategy for its clinical application is addressed, which provides a ground for future development of 25HC-based antiviral drugs.
Info Adicional:
Viruses are small intracellular parasites that must invade a living cell to reproduce. There are very few effective antiviral drugs and just for some viral infections. In recent years, some research groups demonstrated the ability of 25-hydroxycholesterol (25HC) to inhibit the replication of several viruses, including human immunodeficiency virus (HIV), hepatitis C virus (HCV) and Zika virus (ZIKV). It has already been shown that this sterol blocks the viral fusion, but the mechanism behind its action has not been clarified. Thus, the first objective of my Ph.D. Thesis was to understand the effects of cholesterol replacement by 25HC at the membrane level, in the process of membrane fusion, as well as the effect of this membrane alterations on the secondary structure of the HIV fusion peptide. We found that the presence of 25HC deeply modifies the biophysical properties of membranes, promoting changes in membrane fluidity and order and altering its dipole potential. Moreover, we demonstrated that 25HC has also an effect on HIV fusion peptide structure. Despite the enlightening results, the use of 25HC as an antiviral therapy has some limitations. With this in mind, our proposal was to study fusion inhibitor peptides conjugated to 25-hydroxycholesterol, turning the sterol more specific towards the target. Additionally, the conjugation of a lipid moiety, with antiviral activity, to fusion inhibitor peptides should improve their pharmacokinetic and pharmacodynamic properties and turn the peptide less prone to mutations. Therefore, we characterized the interaction of two antiviral peptides (against human immunodeficiency virus and measles virus), both conjugated to 25HC, with biomembranes model systems and peripheral blood cells. Overall, in this Thesis are presented several results that contribute to a better knowledge of the mechanisms associated with the antiviral functions of 25HC. In addition, a new strategy for its clinical application is addressed, which provides a ground for future development of 25HC-based antiviral drugs.
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