Abstract
Classical target-based, high-throughput screening has been useful for the identification of inhibitors for known molecular mechanisms involved in the HIV life cycle. In this study, the development of a cell-based assay that uses a phenotypic drug discovery approach based on automated high-content screening is described. Using this screening approach, the antiviral activity of 26,500 small molecules from a relevant chemical scaffold library was evaluated. Among the selected hits, one sulfonamide compound showed strong anti-HIV activity against wild-type and clinically relevant multidrug resistant HIV strains. The biochemical inhibition, point resistance mutations and the activity of structural analogs allowed us to understand the mode of action and propose a binding model for this compound with HIV-1 reverse transcriptase.
Highlights
Since the first description of the acquired immunodeficiency syndrome (AIDS) in 1981, the human immunodeficiency virus (HIV)/AIDS pandemic has spread throughout the world, killing half of the 60 million people infected far [1,2]
Anti-HIV medications currently approved by the U.S Food and Drug Administration fall into six therapeutic classes: (i) Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs), (ii) Nucleoside Reverse Transcriptase Inhibitors (NRTIs), (iii) Protease Inhibitors (PIs), (iv) Fusion Inhibitors, (v) Entry Inhibitors and (vi) Integrase Inhibitors [3]
We tested dimethyl sulfoxide (DMSO) tolerance because this typical carrier substance is used during drug screens
Summary
Since the first description of the acquired immunodeficiency syndrome (AIDS) in 1981, the human immunodeficiency virus (HIV)/AIDS pandemic has spread throughout the world, killing half of the 60 million people infected far [1,2]. The recommended treatment strategy Highly Active Antiretroviral Therapy - combines three or more anti-HIV medications in a daily regimen and has considerably improved the quality of life for infected people by delaying the progression of the disease and reducing disabilities, making HIV/ AIDS a chronic disease, not a death sentence [3,4]. These medications do not cure HIV infection, and individuals taking these medications can still transmit HIV to others [4,5,6,7,8]. Adverse drug side effects, which are frequently associated with long-term treatment, and the rapid increase of viral strains that are resistant to available antiretroviral drugs threaten the success of current HIV treatment, emphasizing the importance of developing alternative anti-HIV compounds [3,4,9,10]
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