Avirulins, a Novel Class of HIV-1 Reverse Transcriptase Inhibitors Effective in the Female Reproductive Tract Mucosa

Autor: Alisha Kellner, Alexander M. Cole, Christine F. Chong, Michelle D. Cherne, Jesse Hall, Amy L. Cole
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Zdroj: Viruses, Vol 11, Iss 5, p 408 (2019)
Viruses
Volume 11
Issue 5
ISSN: 1999-4915
Popis: While extensive research efforts have decreased human immunodeficiency virus (HIV) transmissions and mortalities, new challenges have arisen in the fight to eradicate HIV. Drug resistance to antiretroviral therapy threatens infected individuals, while the prevalence of heterosexual transmission creates an urgent need for therapies effective in the female reproductive tract (FRT) mucosa. We screened a library of 2095 small molecule compounds comprising a unique chemical space, purchased from Asinex Corporation, for antiviral activity against human immunodeficiency virus type 1 (HIV-1) strain BaL and identified several molecular representatives of a unique class of HIV-1 inhibitors, which we termed &ldquo
Avirulins.&rdquo
We determined that Avirulins were active against clinical isolates of HIV-1 from genetically variant subtypes, several of which have reduced sensitivity to other antivirals. Avirulins displayed specific dose-dependent inhibition of the HIV-1 drug target, reverse transcriptase (RT). Avirulins were effective against several nucleoside RT-inhibitor resistant strains of HIV-1, as well as one nonnucleoside RT-inhibitor resistant strain containing a 106A mutation, suggesting a noncompetitive mechanism of action. Drugs, which are damaging to the FRT, can increase the risk of HIV-1 transmission. We therefore explored the cytotoxicity of Avirulins against epithelial cells derived from the FRT and found no significant toxicity, even at the highest concentrations tested. Importantly, Avirulin antiviral activity was not diminished in human cervico&ndash
vaginal fluid, suggesting retained potency in the milieu of the FRT. Based on these promising results, Avirulins should be valuable chemical scaffolds for development into next-generation treatments and preventatives that target HIV-1.
Databáze: OpenAIRE
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