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Antimicrobials during Pregnancy
Published in “Bert” Bertis Britt Little, Drugs and Pregnancy, 2022
An integrase inhibitor, elvitegravir is used to treat HIV infection. 213 women used it during the first trimester (Antiretroviral Registry, 2018). The frequency of congenital anomalies was not increased above background (www.apregistry.com/forms/interim_report.pdf).
Human immunodeficiency virus (HIV)
Published in Hung N. Winn, Frank A. Chervenak, Roberto Romero, Clinical Maternal-Fetal Medicine Online, 2021
Richard Basilan, William Salzer
Nucleoside reverse transcriptase inhibitors (NRTIs) were the first drugs active against HIV to be developed with the introduction of zidovudine or azidothymidine in 1987. The NRTIs are nucleoside analogs and require intracellular phosphorylation in order to become active. They are incorporated into the DNA chain and terminate DNA chain elongation by acting as nonactive substrates for the viral reverse transcriptase. Nonnucleoside reverse transcriptase inhibitors (NNRTIs), on the other hand, bind to the reverse transcriptase enzyme and induce conformational changes at the active site, thereby rendering the enzyme nonfunctional. Protease inhibitors (PIs) target the viral protease, an enzyme required for cleavage of precursor proteins (gag and gag-pol), thereby preventing the final assembly of the inner core of viral particles (22). Entry inhibitors block the penetration of HIV virions into their target cells by either preventing fusion (enfuvirtide) or by blocking the CCR5 coreceptor required for entry (Maraviroc). A newer class of ARVs act by inhibiting the enzyme required for integration of the transcribed viral genome into the host DNA (integrase), aptly named integrase inhibitors. Available ARV agents are summarized in Table 1.
HIV
Published in Meera Chand, John Holton, Case Studies in Infection Control, 2018
Integration is carried out by the viral enzyme integrase (INT) and ensures that the viral genome is present within the cell until it dies. Cell death is frequently the consequence of HIV-1 infection. In a small subset of cells that evade this fate, however, the virus can remain dormant and is able to reactivate at a later time. This is the reason that combined antiretroviral therapy (cART) is unable to cure patients of HIV-1 infection, as it does not eradicate these integrated viral genomes.
Evaluation of a flavonoid library for inhibition of interaction of HIV-1 integrase with human LEDGF/p75 towards a structure–activity relationship
Published in Annals of Medicine, 2022
Zhi-Hui Yin, Hao-Li Yan, Yu Pan, Da-Wei Zhang, Xin Yan
HIV-1 integrase (IN), a virus-encoded enzyme, plays a vital role in viral replication. IN has no counterparts in mammalian, this is considered an appealing target for anti-HIV-1 drugs [1–3]. IN catalyses the integration of viral DNA into the host genome in a two-step process, 3′-processing and strand transfer [4–6]. The catalytic core domain of IN, critical to its enzymatic function, comprises the acidic triad DDE (D64, D116, E15) motif, which coordinates two magnesium ions [6]. Chelation of the divalent ion can impair the function of IN, providing a good development strategy for IN inhibitors [7]. In fact, three clinically available IN inhibitors (including raltegravir, elvitegravir, and dolutegravir) bind the magnesium ions through the keto-enol carboxyl moiety and form hydrophobic interactions with the DDE motif [8].
Antiretroviral treatment for HIV infection: Swedish recommendations 2019
Published in Infectious Diseases, 2020
Jaran Eriksen, Christina Carlander, Jan Albert, Leo Flamholc, Magnus Gisslén, Lars Navér, Veronica Svedhem, Aylin Yilmaz, Anders Sönnerborg
HIV-drugs are categorized into six groups according to their antiretroviral activity into six groups (Table 1). Cross-resistance is not seldom seen within these groups, but not between groups. Virus entry into the cell can be inhibited by enfuvirtide (which blocks fusion by binding to the viral surface protein gp41), ibalizumab (a monoclonal anti-CD4-antibody that prevents HIV from infecting the cell – currently not available in Sweden) and maraviroc (binding to the cell’s CCR5-receptor thus preventing entry of CCR5-trophic virus). These medicines are rarely used. Nucleoside reverse transcriptase inhibitors (NRTI) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) inhibit reverse transcriptase (RT) (which synthesizes HIV DNA using HIV RNA as a template). Integrase inhibitors (INSTI) block the virus-specific enzyme integrase, thereby preventing viral DNA from being integrated into cellular DNA. Finally, protease inhibitors (PI) inhibit the viral protease and thereby the production of mature virus.
The selenium-containing drug ebselen potently disrupts LEDGF/p75-HIV-1 integrase interaction by targeting LEDGF/p75
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Da-Wei Zhang, Hao-Li Yan, Xiao-Shuang Xu, Lei Xu, Zhi-Hui Yin, Shan Chang, Heng Luo
HIV-1, the virus that causes acquired immune deficiency syndrome (AIDS), is one of the world’s most serious health and development challenges. There were approximately 36.7 million people worldwide living with HIV/AIDS at the end of 20161. During the last three decades, significant progress has been made in the medical treatment of patients with HIV-1 infection; however, the rapid emergence of drug resistance together with toxicity and patient compliance limit the use of antiviral drugs, there remains a need for discovery of new antiviral agents2,3. HIV-1 integrase (IN), an essential enzyme encoded at the 3′-end of the HIV pol gene, is an attractive target for chemotherapeutic intervention4,5. IN is a multifaceted player in HIV-1 infection. Apart from its catalytic activity composed of 3′ processing and strand transfer, investigation of mutagenesis in IN and the mode of action of allosteric IN inhibitor (ALLINI) revealed that IN also play several other biological roles in HIV-1 life cycle, including virion morphogenesis, virus particle uncoating and PIC nuclear import6.