While extensive research efforts have decreased human immunodeficiency virus (HIV)\ntransmissions and mortalities, new challenges have arisen in the fight to eradicate HIV. Drug\nresistance to antiretroviral therapy threatens infected individuals, while the prevalence of heterosexual\ntransmission creates an urgent need for therapies effective in the female reproductive tract (FRT)\nmucosa. We screened a library of 2095 small molecule compounds comprising a unique chemical\nspace, purchased from Asinex Corporation, for antiviral activity against human immunodeficiency\nvirus type 1 (HIV-1) strain BaL and identified several molecular representatives of a unique class of\nHIV-1 inhibitors, which we termed â??Avirulins.â?We determined that Avirulins were active against\nclinical isolates of HIV-1 from genetically variant subtypes, several of which have reduced sensitivity\nto other antivirals. Avirulins displayed specific dose-dependent inhibition of the HIV-1 drug target,\nreverse transcriptase (RT). Avirulins were effective against several nucleoside RT-inhibitor resistant\nstrains of HIV-1, as well as one nonnucleoside RT-inhibitor resistant strain containing a 106A mutation,\nsuggesting a noncompetitive mechanism of action. Drugs, which are damaging to the FRT, can increase\nthe risk of HIV-1 transmission. We therefore explored the cytotoxicity of Avirulins against epithelial\ncells derived from the FRT and found no significant toxicity, even at the highest concentrations tested.\nImportantly, Avirulin antiviral activity was not diminished in human cervicoâ??vaginal fluid, suggesting\nretained potency in the milieu of the FRT. Based on these promising results, Avirulins should be\nvaluable chemical scaffolds for development into next-generation treatments and preventatives that\ntarget HIV-1.
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