ABSTRACT
M ASA NO RI BABA,* JA N BA LZA RIN I,+ R U D I PA U W ELS,+ a n d ER IK DE C L E R C Q +
*Division of Human Retroviruses, Center for Chronic Viral Diseases, Faculty of Medicine, Kagoshima University, Kagoshima 890, Japan and
+Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium
INTRODUCTION
HIV-1-specific reverse transcriptase inhibitors encompass all those compounds that, because of a specific interaction with HIV-1 reverse transcriptase (RT), inhibit the replication of HIV-1 but no t that of HIV-2 or any other retrovirus. These HIV-1-specific RT inhibitors have also been referred to as NNRTIs (non nucleoside reverse transcriptase inhibitors) and should be distinguished from the nucleoside type of RT inhibitors, such as the 2',3-dideoxynucleosides (ddNs) azidothymidine (AZT), dideoxyinosine (DDI) and dideoxycytidine (DDC), which are no t specifically inhibitory to HIV-1 but also inhibit the replication of HIV-2 and other retroviruses. In contrast with the ddNs, which need to be phosphorylated intracellularly to their 5-triphosphate form (ddNTP) before they interact with the substrate (dNTP) binding site, the NNRTIs do no t require any intracellular metabolism to interact with their target, non substrate binding site at the reverse transcriptase. Some NNRTIs bind with such high affinity/specificity to the HIV-1 RT that they achieve selectivity indexes of 10,000-100,000 in cell culture, i.e. they inhibit HIV-1 replication at concentrations that are 10,000 to 100,000-fold lower than the concentrations needed to affect the viability of the host cells.
