Ribonuclease H inhibitors: Structural and molecular biology

Abstract

PR, IN, and RT are the only enzymes encoded by the HIV genome, and all are targeted by antiviral therapeutic agents (De Clercq 2009). HIV PR cleaves viral polyprotein precursors to produce mature virus and is targeted by PR inhibitors saquinavir, ritonavir, and several others. IN is required for assimilation of viral DNA into the genome of the infected cell and is targeted by raltegravir. A second IN inhibitor, elvitegravir, is currently in the latter stages of clinical trials. RT possesses two enzymatic activities: DNA polymerase and RNase H. The former is targeted by both NRTIs (e.g., didanosine, or 2′,3′-dideoxyinosine) and NNRTIs (e.g., nevirapine, efavirenz) (Ruane and DeJesus 2004). Of the 25 anti-HIV compounds in clinical use today, 12 target the multifunctional RT enzyme. However, none of these inhibitors target the RNase H activity of RT, despite it being absolutely essential for synthesis of preintegrative viral DNA (Schatz et al. 1989). In this chapter, various aspects of HIV-1 RT-associated RNase H and its inhibition will be discussed, including (i) the structure of HIV-1 RT, with emphasis on the RNase H domain; (ii) the two-metal-ion-dependent mechanism of RNase H cleavage; and (iii) efforts and progress toward developing potent and specific inhibitors of the lone untargeted HIV enzymatic function.