Chamoun Emanuelli, Ana M (2014-08). Characterization of Viral Entry Inhibitors. Doctoral Dissertation. Thesis uri icon

abstract

  • Hepatitis C virus (HCV), Human Immunodeficiency virus (HIV) and Herpes Simplex virus (HSV) are pathogenic viruses known to cause liver disorder, acquired immunodeficiency and skin lesions, respectively. Although current therapies have played substantial roles in the fight against these pathogens, their use is limited and for the most part does not result in viral eradication. Moreover, most antivirals target viral encoded structures which overtime foster the development of resistant strains. Hence, antivirals aimed at preventing initial infection represent a promising strategy for viral combat. This dissertation focuses on the characterization of viral entry inhibitors and their potential use. The first compounds evaluated come from the phenothiazines family, widely used as antipsychotic drugs. Phenothiazines were shown to suppress HCV entry by intercalating into cholesterol-rich membrane domains of target cells thus reducing viral-host fusion. The second candidates studied are two members of the H1-anthistamines currently used for allergy treatment. Both compounds strongly reduce HCV entry, likely at the fusion step, and its inhibition was associated with cholesterol content in the virion and host cells, pointing to the use of an NPC1L1-receptor dependent mechanism. Lastly, we evaluated the antiviral activity of PD 404,182 (PD) as an alternate treatment for HCV-HIV coinfected patients as well as its potential use as an anti-HIV microbicide. PD is able to reduce viral entry of the three pathogens through physical disruption of virions releasing the nucleic acids into the surrounding medium. Moreover, PD possesses several qualities pointing to its use as a potential microbicide.
  • Hepatitis C virus (HCV), Human Immunodeficiency virus (HIV) and Herpes Simplex virus (HSV) are pathogenic viruses known to cause liver disorder, acquired immunodeficiency and skin lesions, respectively. Although current therapies have played substantial roles in the fight against these pathogens, their use is limited and for the most part does not result in viral eradication. Moreover, most antivirals target viral encoded structures which overtime foster the development of resistant strains. Hence, antivirals aimed at preventing initial infection represent a promising strategy for viral combat.

    This dissertation focuses on the characterization of viral entry inhibitors and their potential use. The first compounds evaluated come from the phenothiazines family, widely used as antipsychotic drugs. Phenothiazines were shown to suppress HCV entry by intercalating into cholesterol-rich membrane domains of target cells thus reducing viral-host fusion.

    The second candidates studied are two members of the H1-anthistamines currently used for allergy treatment. Both compounds strongly reduce HCV entry, likely at the fusion step, and its inhibition was associated with cholesterol content in the virion and host cells, pointing to the use of an NPC1L1-receptor dependent mechanism.

    Lastly, we evaluated the antiviral activity of PD 404,182 (PD) as an alternate treatment for HCV-HIV coinfected patients as well as its potential use as an anti-HIV microbicide. PD is able to reduce viral entry of the three pathogens through physical disruption of virions releasing the nucleic acids into the surrounding medium. Moreover, PD possesses several qualities pointing to its use as a potential microbicide.

publication date

  • August 2014