Raltegravir
M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson in Kucers’ The Use of Antibiotics, 2017
HIV integrase participates in the successful completion of the HIV-1 viral life cycle by mediating the integration of HIV-1 DNA into the host genome, making inhibitors of this enzyme attractive agents for the treatment of HIV/AIDS. HIV-1 integrase is encoded as one of the gene products of the HIV-1 pol gene and is a member of the polynucleotidyl transferase (recombinase) protein superfamily (Mizuuchi, 1997). Based on biochemical, structural, and phylogenetic analyses, HIV-1 integrase can be subdivided into three protein domains. The largest domain of HIV-1 integrase is the catalytic core. This domain contains a highly conserved triad of acidic residues, the D,D-35-E motif, which play a key role in the catalytic activities of the enzyme (Engelman and Craigie, 1992; Kulkosky et al., 1992).
Physiology and Growth
Paul Pumpens in Single-Stranded RNA Phages, 2020
Intriguingly, expression of the human immunodeficiency virus-1 integrase in E. coli, at levels that had no effect on bacterial cell growth, blocked plaque formation by the phages R17, Qβ, and PRR1, as well as M13, while plaque formation by phages having double-stranded DNA genomes was unaffected (Levitz et al. 1994). An early stage in infection was affected by the integrase and it was suggested that the integrase interacted in vivo with phage nucleic acid, while the putative effect on the pili was excluded. This conclusion was supported by studies in which the integrase was shown to have a DNA-binding activity in its C-terminal portion. This portion of the integrase was both necessary and sufficient for the interference of plaque formation by the phages R17 and M13 (Qβ and PRR1 were not tested). Expression of the N-terminal portion of the integrase at the same level as the intact integrase had little effect on the phage growth, indicating that the expression of foreign protein in general was not responsible for the inhibitory effect (Levitz et al. 1994).
Human immunodeficiency virus (HIV)
Hung N. Winn, Frank A. Chervenak, Roberto Romero in Clinical Maternal-Fetal Medicine Online, 2021
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.
The dawn of precision medicine in HIV: state of the art of pharmacotherapy
Published in Expert Opinion on Pharmacotherapy, 2018
Ying Mu, Sunitha Kodidela, Yujie Wang, Santosh Kumar, Theodore J. Cory
HIV integrase inhibits integration of viral genome into chromosomal DNA. Raltegravir (RAL), dolutegravir (DTG), and elvitegravir (EVG) have been approved by FDA. RAL is administered 400 mg twice daily and the half-life is 7–12 h [46]. After 12 h, the plasma RAL concentration is 63 ng/ml. Except for patients over 60 years old and younger who has reduced creatinine clearance of RAL, there is no need to adjust RAL dosage based on sex, gender, body weight, hepatic, or renal function impairment [7]. A new once-daily RAL (2 × 600 mg once-daily) plus FTC/TDF was proven non-inferior than the original version (400 mg twice daily) plus FTC/TDF [47]. RAL is metabolized by UGT1A1. The polymorphisms in UGT1A1 may not be clinically relevant in dose adjustment of RAL [48,49]. Similarly, Calcagno et al. also reported that variants in genes encoding RAL transporters (ABCB1 3435, SLCO1A2, ABCC2, and SLC22A6) and hepatocyte nuclear factor 4α did not account for high inter-patient variability of RAL CSF concentrations in HIV-infected subjects [50]. The pharmacodynamic and pharmacogenomic data for commonly used INSTIs are summarized in Tables 1 and 2.
Frontiers of metal-coordinating drug design
Published in Expert Opinion on Drug Discovery, 2021
Giulia Palermo, Angelo Spinello, Aakash Saha, Alessandra Magistrato
Finally, magnesium-dependent proteins and ribozymes are widespread and promote the metabolism of nucleic acids in genome regulatory processes [17,18]. Among these, Mg2+-dependent pharmacological targets are (i) the flap endonuclease 1 (FEN1), an enzyme that removes the DNA and RNA flaps formed during replication and repair and is targeted by anticancer drugs [19,20]; (ii) HIV integrase, which inserts the viral genome into the host cell and is targeted by antiviral compounds [21]; (iii) the GTPase enzymes, which are critically linked with cellular differentiation, proliferation, division, and movement by regulating signal transduction. Their activity in many infiltrative (brain, ovarian, and melanoma) cancers can be inhibited by small-molecules binding to their Mg2+ ion cofactor [22].
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.
Related Knowledge Centers
- Enzyme
- Macromolecular Assembly
- Recombinase
- Retrovirus
- HIV
- Pre-Integration Complex
- Cell
- Site-Specific Recombination
- Site-Specific Recombinase Technology
- Lambda Phage