Abstract
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 “Avirulins.” 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–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.
Highlights
Human immunodeficiency virus (HIV), the causative agent of acquired immune deficiency syndrome (AIDS), destroys the host immune system by invasion and subsequent destruction ofCD4+ lymphocytes, leading to death by opportunistic infections [1,2,3]
A library of 2095 small-molecule compounds obtained from Asinex Corporation were screened for antiviral activity against human immunodeficiency virus type 1 (HIV-1) BaL at 50 μM using the luciferase-based reporter HeLa-derived cell line, TZM-bl [28]
We performed an extensive in silico database search for similar structures using the chemical search program, SciFinder, of the Chemical Abstract System (CAS) REGISTRYSM, which contains more than 100 million substances [32]
Summary
Human immunodeficiency virus (HIV), the causative agent of acquired immune deficiency syndrome (AIDS), destroys the host immune system by invasion and subsequent destruction ofCD4+ lymphocytes, leading to death by opportunistic infections [1,2,3]. At the onset of the HIV/AIDS crisis, patients succumbed to these AIDS related complications within 10 years of infection [4]. The development of HIV-1 antiretroviral therapies (ART) vastly reduced AIDS related complications and mortality and has changed HIV infection from a fatal to chronic disease for those with access to treatment [5]. Viruses 2019, 11, 408 subsequent increase in transmitted drug resistance mutations, giving newly infected patients fewer treatment options [7]. This has created the urgent demand for novel therapeutics and preventatives to combat drug resistance and prevent sexual transmission
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