Nucleoside Analogue Inhibitors of Human Immunodeficiency Virus Reverse Transcriptase

More than 20 different antiretroviral agents have been approved for human immunodeficiency virus (HIV) treatment. These compounds target distinct stages in the life cycle of this retrovirus that include (i) its entry into the cytoplasm, which marks the beginning of the infection; (ii) the process of reverse transcription, i.e., the conversion of the single-stranded RNA genome into double-stranded DNA; (iii) the integration of proviral, double-stranded DNA into the host chromosome; and (iv) the processing of viral precursor proteins at later stages. These steps are vital for viral replication, and with the exception of the entry process, each of the aforementioned reactions involves viral enzymes, i.e., the reverse transcriptase (RT), the integrase, and the protease, respectively, that can be targeted by antiretroviral drugs. This chapter focuses on nucleoside analogue RT inhibitors (NRTIs) in the context of mechanisms of action and resistance and on the implications for the development of future strategies designed to counteract resistance. All approved NRTIs show a broad spectrum of antiviral activity against HIV-1, HIV- 2, and sometimes even hepatitis B virus (HBV), which points to structurally highly related active sites. A given mutation or mutational cluster can affect susceptibility to different NRTIs to various degrees, which makes it difficult to group the mutations. It will be interesting to investigate how established and novel NRTIs can be most effectively combined with new classes of compounds with the ultimate goal of further reducing the risk of resistance development, while maintaining high standards regarding problems associated with toxicities and dosing.