Discovery and development of integrase inhibitors

The first human immunodeficiency virus (HIV) case was reported in the United States in the early 1980s. Many drugs have been discovered to treat the disease but mutations in the virus and resistance to the drugs make development difficult. Integrase is a viral enzyme that integrates retroviral DNA into the host cell genome. Integrase inhibitors are a new class of drugs used in the treatment of HIV. The first integrase inhibitor, raltegravir, was approved in 2007 and other drugs were in clinical trials in 2011.

In the 1980s an infectious disease started to plague human civilization. The coexistence of viruses and humans is a fight for survival for both because the invaders can kill the human but in doing so eliminate their own host. The body uses its immune system to protect itself from bacteria, viruses and other disease-causing beings, and when it fails to do so immunodeficiency diseases occur. One such disease is acquired immunodeficiency syndrome (AIDS) which is most commonly a result of an infection by the human immunodeficiency virus (HIV). Two closely related types of HIV have been identified, HIV-1 and HIV-2. While HIV-2 is spreading in India and West Africa, HIV-1 is more virulent and the number one cause of AIDS worldwide. Though some of the patients have different results in most cases people infected with HIV go on to develop AIDS and ultimately die of opportunistic infections or cancer. Integration to the retroviral genome is critical for gene expression and viral replication. The viral genome is reversely transcribed into the DNA of the infected cell by viral reverse transcriptase, the DNA is then integrated into the host-cell chromosomes with the aid of the viral integrase. RNA transcripts are produced from integrated viral DNA and serve both as mRNAs to direct the synthesis of viral proteins and later as RNA genomes of the new viral particles.Viral particles escape from the cell by budding from the plasma membrane, each enclosed in a membrane envelope. In this process HIV-1 integrase is essential and therefore a very promising target for anti-AIDS drug design. Selective drug design is a possibility as HIV-1 integrase has no known cellular equivalent. Many integrase inhibitors have been discovered and designed but only a few of the molecules were developed further and got as far as phase II or phase III of clinical trials. Raltegravir (brand name Isentress) was granted accelerated approval from the U.S. Food and Drug Administration (FDA) in October 2007 and from EMEA (now EMA) in December 2007. It was marketed as an antiretroviral drug (ARV) for HIV-1 infected adults who had already been exposed to a minimum of three ARV classes and showed multi-drug resistance. In general there are two main groups of integrase inhibitors; Integrase Strand Transfer inhibitors (INSTI) and Integrase Binding Inhibitors (INBI). INSTIs restrain the binding of pre-integration complex (PIC) and host DNA and INBIs restrain integrase and viral DNA binding. Raltegravir is an INSTI integrase inhibitor which inhibits both HIV-1 and HIV-2 replication. It is more potent than other previously known integrase inhibitors as well as causing less side effects. Raltegravir, Elvitegravir, and Dolutegravir are the only HIV-1 integrase inhibitor being used to treat HIV infections elvitegravir and S/GSK1349572.

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