Nonnucleoside reverse transcriptase inhibitors (NNRTIs)

Abstract

HIV is a retrovirus; the retroviral life cycle is characterized by two specific steps: (1) the conversion of the single-stranded RNA genome found in the virion into double-stranded DNA by the viral enzyme reverse transcriptase (RT) and (2) the subsequent insertion of this DNA copy into the host genome by the viral enzyme integrase. Both of these steps are essential for the viral life cycle; both are targets for important anti-HIV drugs. There are two broad classes of drugs that block reverse transcription: nucleoside/nucleotide analogs (NRTIs) and nonnucleoside inhibitors (NNRTIs). The conversion of the RNA genome into DNA involves the collaboration of the two enzymatic activities of RT, a DNA polymerase that can copy either an RNA or a DNA substrate, and an RNase H that cleaves RNA if, and only if, it is part of an RNA/DNA duplex (see Chap. 1). The first anti-HIV drugs to be identified and used in clinic were NRTIs (see Chap. 2); the second class were the NNRTIs. NNRTIs bind to RT and allosterically block its polymerase activity. NRTIs and NNRTIs are both used extensively to treat HIV-1 infected patients in the highly active antiviral therapies (HAART); both classes of drugs hold the promise that they can be used to reduce the transmission of the virus (Chap. 15). Because HIV infections cannot be cured by drug treatment, patients who begin drug therapy are usually on therapy for the rest of their lives. This makes the problem of developing anti-HIV drugs particularly challenging and places special emphasis on two fundamental considerations: the toxicity of long-term therapy and the development of resistance. As will be discussed in more detail later, for NNRTIs, the development of resistance has been the larger issue; in contrast to NRTIs, the toxicity of most NNRTIs has been a lesser concern. This chapter will discuss NNRTIs and will be divided into three parts: (1) mechanism of action, (2) the problem of resistance, and (3) a brief look forward at what the future might hold, both in terms of the development of new NNRTIs and in their uses.