What Is an Integrase Inhibitor?

Integrase inhibitors refer to drugs that inhibit integrase, that is, to inhibit the process of retroviral replication and block the integration of catalytic viral DNA and host chromosomal DNA. A large number of HIV-1 integrase inhibitors have been identified. Some of these compounds have been shown to selectively inhibit HIV-1 integrase and block viral replication. The two most influential inhibitors are phthalates. Polyhydroxy aromatic compounds of phenols and recently reported aryl -diketonates.

Integrase inhibitors refer to drugs that inhibit integrase, that is, to inhibit the process of retroviral replication and block the integration of catalytic viral DNA and host chromosomal DNA. A large number of HIV-1 integrase inhibitors have been identified. Some of these compounds have been shown to selectively inhibit HIV-1 integrase and block viral replication. The two most influential inhibitors are phthalates. Polyhydroxy aromatic compounds of phenols and recently reported aryl -diketonates.

HIV integrase inhibitors are a new type of anti-HIV / AIDS drug, which can be used in combination with other antiretroviral drugs to effectively treat HIV infection, and it is not easy to develop resistance in the clinic.

Definition of integrase inhibitor

HIV-1 integrase is an essential enzyme for retroviral replication and has no analogs in human cells, making it an attractive and reasonable target for the treatment of AIDS. Integrase inhibitors refer to drugs that inhibit integrase, that is, to inhibit the process of retroviral replication and block the integration of catalytic viral DNA and host chromosomal DNA. A large number of HIV-1 integrase inhibitors have been identified. Some of these compounds have been shown to selectively inhibit HIV-1 integrase and block viral replication. The two most influential inhibitors are phthalates. Polyhydroxy aromatic compounds of phenols and recently reported aryl -diketonates.

HIV integrase inhibitors (integrase inhibitors) are a new type of anti-HIV / AIDS drugs, which can be used in combination with other antiretroviral drugs to effectively treat HIV infection, and it is not easy to develop drug resistance in clinical.

Integrase inhibitor discovery and development

In the 1980s, an infectious disease began to haunt human civilization. The coexistence of viruses and humans is fighting each other for survival because intruders can kill people but are also destroying their own hosts. The body uses its immune system to protect itself from bacteria, viruses, and other diseases that cause immunodeficiency when it fails. One such disease is called acquired immunodeficiency syndrome. AIDS is the most common result of being infected with 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 deadly and the number one cause of AIDS in the world. Although some patients have different results, in most cases HIV infection people continue to develop AIDS and eventually die of opportunistic infections or cancer. Integration is critical for the retroviral genome for gene expression and viral replication. The viral genome is reversely transcribed into the DNA of infected cells by viral reverse transcriptase, and then integrated into the host cell chromosome by means of viral integrase DNA. Generate RNA transcription from integrated viral DNA and use, for example, mRNAs to direct viral protein synthesis and later serve as a new viral particle RNA genome. Escaping from the plasma membrane through the budding virus particles escapes from the cells, each enclosed within a membrane envelope. HIV-1 integrase is important in this process and therefore anti-AIDS drug designs are very promising targets. Selective drug designs have no known cellular equivalent as HIV-1 integrase possibilities. Many integrase inhibitors have been discovered and designed but only a few molecules have been further developed and obtained as far as phase II or III of clinical trials. The FDA granted Latiravir (trade name Isentress®) accelerated approval in October 2007 and from EMEA (now EMA) in December 2007. It is recognized as an antiviral drug (ARV) for HIV-1 adulthood and has been exposed to at least three antiviral types and has shown multidrug resistance to market. In general, there are two main groups of integrase inhibitors; integrase chain transfer inhibitors (INSTI) and integrase binding inhibitors (INBI). INSTIs inhibit the binding of pre-integration complex (PIC) to host DNA and INBIs inhibit the binding of integrase to viral DNA. Latiravir is an INSTI integrase inhibitor that inhibits both HIV-1 and HIV-2 replication. It is stronger than other previously known integrase inhibitors and causes milder side effects. Latiravir is the only HIV-1 integrase inhibitor currently being used to treat HIV infection, but other drugs are in clinical trials, such as elvitegravir and S / GSK1349572.

Integrase inhibitor mechanism of action

The mechanism of HIV integrase inhibitor is currently used in clinical HIV / AIDS drugs mainly targeting HIV reverse transcriptase and protease, but there are problems such as large adverse drug reactions and prone to drug resistance. HIV integrase is a protein composed of three parts: N-terminal domain, catalytic core domain and C-terminal domain. It is one of the four key enzymes in the process of HIV replication. One. HIV uses this enzyme to integrate its own genetic material into infected cells. Viral DNA is integrated into human host genes. The integration process is completed through 3-processing and chain transfer [5]. In this way, viral DNA is inserted into the host chromosome under the catalysis of integrase, and uses the function and raw materials of host cell gene replication to complete HIV replication and infection. HIV integrase inhibitors are also called HIV integrase strand transfer inhibitors. They inhibit HIV integrase and effectively inhibit the replication of HIV in the body without harming normal cells. Low toxicity.

HIV Integrase inhibitors approved for clinical use

Cocktail therapy consisting of HIV integrase inhibitors and marketed reversetranscriptase inhibitors, proteaseinhibitors, and fusion inhibitors may address the resistance of single-drug and The problem of cross-resistance will significantly improve the treatment effect of existing HIV drugs and become a new treatment approach and option.

HIV integrase inhibitor drugs that have been approved for marketing and have entered clinical use include: raltegravir, elvitegravir, dolutegravir, and the fixed-dose compound Stribild.

: Integrase inhibitor references:

1.Luo Lijuan, Huang Lu, Zhang Yuqin.Research and application of HIV integrase inhibitor drugs [J] .Chinese Journal of New Drugs and Clinical Medicine, 2014, (Issue 7).

2.Wu Yanbin, Jin Jie, Wang Ruizhen, Liu Jun, Wang Yan, Chen Xiaofang.Synthesis and Activity of HIV-1 Integrase Inhibitors with Didiketonate Structure [J] .China Medical Biotechnology, 2015, (# 5) .