Discovery and development of non-nucleoside reverse-transcriptase inhibitors

Non-nucleoside reverse-transcriptase inhibitors (NNRTIs) are antiretroviral drugs used in the treatment of human immunodeficiency virus (HIV). NNRTIs inhibit reverse transcriptase (RT), an enzyme that controls the replication of the genetic material of HIV. RT is one of the most popular targets in the field of antiretroviral drug development. Non-nucleoside reverse-transcriptase inhibitors (NNRTIs) are antiretroviral drugs used in the treatment of human immunodeficiency virus (HIV). NNRTIs inhibit reverse transcriptase (RT), an enzyme that controls the replication of the genetic material of HIV. RT is one of the most popular targets in the field of antiretroviral drug development. Discovery and development of NNRTIs began in the late 1980s and in the end of 2009 four NNRTI had been approved by regulatory authorities and several others were undergoing clinical development. Drug resistance develops quickly if NNRTIs are administered as monotherapy and therefore NNRTIs are always given as part of combination therapy, the highly active antiretroviral therapy (HAART). Acquired immunodeficiency syndrome (AIDS) is a leading cause of death in the world. It was identified as a disease in 1981. Two years later the etiology agent for AIDS, the HIV was described. HIV is a retrovirus and has two major serotypes, HIV-1 and HIV-2. The pandemic mostly involves HIV-1 while HIV-2 has lower morbidity rate and is mainly restricted to western Africa. In the year 2009 over 40 million people were infected worldwide with HIV and the number keeps on growing. The vast majority of infected individuals live in the developing countries. HIV drugs do not cure HIV infection, but the treatment aims at improving the quality of patients´ lives and decreased mortality. 25 antiretroviral drugs were available in 2009 for the treatment of HIV infection. The drugs belong to six different classes that act at different targets. The most popular target in the field of antiretroviral drug development is the HIV-1 reverse transcriptase (RT) enzyme. There are two classes of drugs that target the HIV-1 RT enzyme, nucleoside/nucleotide reverse-transcriptase inhibitors (NRTIs/NtRTIs) and non-nucleoside reverse-transcriptase inhibitors (NNRTIs). Drugs in these classes are important components of the HIV combination therapy called highly active antiretroviral therapy, better known as HAART. In 1987, the first drug for the treatment of HIV infection was approved by the U.S. Food and Drug Administration (FDA). This was the NRTI called zidovudine. In the late 1980s, during further development of NRTIs, the field of NNRTIs discovery began. The development of NNRTIs improved quickly into the 1990s and they soon became the third class of antiretroviral drugs, following the protease inhibitors. The NNRTIs are HIV-1 specific and have no activity against HIV-2 and other retroviruses. The first NNRTI, nevirapine was discovered by researchers at Boehringer Ingelheim and approved by the FDA in 1996. In the next two years two other NNRTIs were approved by the FDA, delavirdine in 1997 and efavirenz in 1998. These three drugs are so-called first generation NNRTIs. The need for NNRTIs with better resistance profile led to the development of the next generation of NNRTIs. Researchers at Janssens Foundation and Tibotec discovered the first drug in this class, etravirine, which was approved by the FDA in 2008. The second drug in this class, rilpivirine, was also discovered by Tibotec and was approved by the FDA in 2011. In addition to these four NNRTIs several other are in clinical development. Reverse transcriptase (RT) is an enzyme that controls the replication of the genetic material of HIV and other retroviruses. The enzyme has two enzymatic functions. Firstly it acts as a polymerase where it transcribes the single-stranded RNA genome into single-stranded DNA and subsequently builds a complementary strand of DNA. This provides a DNA double helix which can be integrated in the host cell's chromosome. Secondly it has ribonuclease H (Rnase H) activity as it degrades the RNA strand of RNA-DNA intermediate that forms during viral DNA synthesis.