Journal articles: 'HIV-1 Integrase Inhibitors'

1

Dayam, Raveendra, Laith Q. Al-Mawsawi, and Nouri Neamati. "HIV-1 Integrase Inhibitors." Drugs in R & D 8, no. 3 (2007): 155–68. http://dx.doi.org/10.2165/00126839-200708030-00003.

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Liao, Chenzhong, Christophe Marchand, Terrence R. Burke Jr, Yves Pommier, and Marc C. Nicklaus. "Authentic HIV-1 integrase inhibitors." Future Medicinal Chemistry 2, no. 7 (July 2010): 1107–22. http://dx.doi.org/10.4155/fmc.10.199.

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3

Zhao, He, Nouri Neamati, Abhijit Mazumder, Sanjay Sunder, Yves Pommier, and Terrence R. Burke. "Arylamide Inhibitors of HIV-1 Integrase." Journal of Medicinal Chemistry 40, no. 8 (April 1997): 1186–94. http://dx.doi.org/10.1021/jm960449w.

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4

Neamati, Nouri, Jim A. Turpin, Heather E. Winslow, John L. Christensen, Karen Williamson, Ann Orr, William G. Rice, et al. "Thiazolothiazepine Inhibitors of HIV-1 Integrase." Journal of Medicinal Chemistry 42, no. 17 (August 1999): 3334–41. http://dx.doi.org/10.1021/jm990047z.

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5

Korolev, S. P., O. V. Kondrashina, D. S. Druzhilovsky, A. M. Starosotnikov, M. D. Dutov, M. A. Bastrakov, I. L. Dalinger, et al. "Structural-Functional Analysis of 2,1,3-Benzoxadiazoles and Their N-oxides As HIV-1 Integrase Inhibitors." Acta Naturae 5, no. 1 (March 15, 2013): 63–72. http://dx.doi.org/10.32607/20758251-2013-5-1-63-72.

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Human immunodeficiency virus type 1 integrase is one of the most attractive targets for the development of anti-HIV-1 inhibitors. The capacity of a series of 2,1,3-benzoxadiazoles (benzofurazans) and their N-oxides (benzofuroxans) selected using the PASS software to inhibit the catalytic activity of HIV-1 integrase was studied in the present work. Only the nitro-derivatives of these compounds were found to display inhibitory activity. The study of the mechanism of inhibition by nitro-benzofurazans/benzofuroxans showed that they impede the substrate DNA binding at the integrase active site. These inhibitors were also active against integrase mutants resistant to raltegravir, which is the first HIV-1 integrase inhibitor approved for clinical use. The comparison of computer-aided estimations of the pharmacodynamic and pharmacokinetic properties of the compounds studied and raltegravir led us to conclude that these compounds show promise and need to be further studied as potential HIV-1 integrase inhibitors.

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Vandegraaff, Nick, Raman Kumar, Helen Hocking, Terrence R. Burke, John Mills, David Rhodes, Christopher J. Burrell, and Peng Li. "Specific Inhibition of Human Immunodeficiency Virus Type 1 (HIV-1) Integration in Cell Culture: Putative Inhibitors of HIV-1 Integrase." Antimicrobial Agents and Chemotherapy 45, no. 9 (September 1, 2001): 2510–16. http://dx.doi.org/10.1128/aac.45.9.2510-2516.2001.

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ABSTRACT To study the effect of potential human immunodeficiency virus type 1 (HIV-1) integrase inhibitors during virus replication in cell culture, we used a modified nested Alu-PCR assay to quantify integrated HIV DNA in combination with the quantitative analysis of extrachromosomal HIV DNA. The two diketo acid integrase inhibitors (L-708,906 and L-731,988) blocked the accumulation of integrated HIV-1 DNA in T cells following infection but did not alter levels of newly synthesized extrachromosomal HIV DNA. In contrast, we demonstrated that L17 (a member of the bisaroyl hydrazine family of integrase inhibitors) and AR177 (an oligonucleotide inhibitor) blocked the HIV replication cycle at, or prior to, reverse transcription, although both drugs inhibited integrase activity in cell-free assays. Quercetin dihydrate (a flavone) was shown to not have any antiviral activity in our system despite reported anti-integration properties in cell-free assays. This refined Alu-PCR assay for HIV provirus is a useful tool for screening anti-integration compounds identified in biochemical assays for their ability to inhibit the accumulation of integrated HIV DNA in cell culture, and it may be useful for studying the effects of these inhibitors in clinical trials.

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7

Depatureaux, Agnès, Peter K. Quashie, Thibault Mesplède, Yingshan Han, Hannah Koubi, Jean-Christophe Plantier, Maureen Oliveira, Daniela Moisi, Bluma Brenner, and Mark A. Wainberg. "HIV-1 Group O Integrase Displays Lower Enzymatic Efficiency and Higher Susceptibility to Raltegravir than HIV-1 Group M Subtype B Integrase." Antimicrobial Agents and Chemotherapy 58, no. 12 (September 15, 2014): 7141–50. http://dx.doi.org/10.1128/aac.03819-14.

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ABSTRACTHIV-1 group O (HIV-O) is a rare HIV-1 variant characterized by a high number of polymorphisms, especially in the integrase coding region. As HIV-O integrase enzymes have not previously been studied, our aim was to assess the impact of HIV-O integrase polymorphisms on enzyme function and susceptibility to integrase inhibitors. Accordingly, we cloned and purified integrase proteins from each of HIV-1 group O clades A and B, an HIV-O divergent strain, and HIV-1 group M (HIV-M, subtype B), used as a reference. To assess enzymatic function of HIV-O integrase, we carried out strand transfer and 3′ processing assays with various concentrations of substrate (DNA target and long terminal repeats [LTR], respectively) and characterized these enzymes for susceptibility to integrase strand transfer inhibitors (INSTIs) in cell-free assays and in tissue culture, in the absence or presence of various concentrations of several INSTIs. The inhibition constant (Ki) and 50% effective concentration (EC50) values were calculated for HIV-O integrases and HIV-O viruses, respectively, and compared with those of HIV-M. The results showed that HIV-O integrase displayed lower activity in strand transfer assays than did HIV-M enzyme, whereas 3′ processing activities were similar to those of HIV-M. HIV-O integrases were more susceptible to raltegravir (RAL) in competitive inhibition assays and in tissue culture than were HIV-M enzymes and viruses, respectively. Molecular modeling suggests that two key polymorphic residues that are close to the integrase catalytic site, 74I and 153A, may play a role in these differences.

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8

Suzuki, Shintaro, Emiko Urano, Chie Hashimoto, Hiroshi Tsutsumi, Toru Nakahara, Tomohiro Tanaka, Yuta Nakanishi, et al. "Peptide HIV-1 Integrase Inhibitors from HIV-1 Gene Products." Journal of Medicinal Chemistry 53, no. 14 (July 22, 2010): 5356–60. http://dx.doi.org/10.1021/jm1003528.

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9

Burke, Terrence R. Jr, Mark Fesen, Abhijit Mazumder, Jessie Yung, Jian Wang, Adelaide M. Carothers, Dezider Grunberger, John Driscoll, Yves Pommier, and Kurt Kohn. "Hydroxylated Aromatic Inhibitors of HIV-1 Integrase." Journal of Medicinal Chemistry 38, no. 21 (October 1995): 4171–78. http://dx.doi.org/10.1021/jm00021a006.

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10

Neamati, Nouri. "Dipyrimidine-based inhibitors of HIV-1 integrase." Expert Opinion on Investigational Drugs 12, no. 2 (February 2003): 289–92. http://dx.doi.org/10.1517/13543784.12.2.289.

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11

Lataillade, Max, and Michael J. Kozal. "The Hunt for HIV-1 Integrase Inhibitors." AIDS Patient Care and STDs 20, no. 7 (July 2006): 489–501. http://dx.doi.org/10.1089/apc.2006.20.489.

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12

Zhao, He, Nouri Neamati, Sanjay Sunder, Huixiao Hong, Shaomeng Wang, George W. A. Milne, Yves Pommier, and Terrence R. Burke. "Hydrazide-Containing Inhibitors of HIV-1 Integrase†." Journal of Medicinal Chemistry 40, no. 6 (March 1997): 937–41. http://dx.doi.org/10.1021/jm960755+.

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13

Wai, John S., Boyoung Kim, Thorsten E. Fisher, Linghang Zhuang, Mark W. Embrey, Peter D. Williams, Donnette D. Staas, et al. "Dihydroxypyridopyrazine-1,6-dione HIV-1 integrase inhibitors." Bioorganic & Medicinal Chemistry Letters 17, no. 20 (October 2007): 5595–99. http://dx.doi.org/10.1016/j.bmcl.2007.07.092.

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14

Dayam, Raveendra, Jinxia Deng, and Nouri Neamati. "HIV-1 integrase inhibitors: 2003–2004 update." Medicinal Research Reviews 26, no. 3 (2006): 271–309. http://dx.doi.org/10.1002/med.20054.

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15

Dayam, Raveendra, Rambabu Gundla, Laith Q. Al-Mawsawi, and Nouri Neamati. "HIV-1 integrase inhibitors: 2005–2006 update." Medicinal Research Reviews 28, no. 1 (2007): 118–54. http://dx.doi.org/10.1002/med.20116.

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16

Ramkumar, Kavya, Erik Serrao, Srinivas Odde, and Nouri Neamati. "HIV-1 integrase inhibitors: 2007-2008 update." Medicinal Research Reviews 30, no. 6 (February 4, 2010): 890–954. http://dx.doi.org/10.1002/med.20194.

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17

Lee, Jae Yeol, Jang Hyun Park, Sook Ja Lee, Hokoon Park, and Yong Sup Lee. "Styrylquinazoline Derivatives as HIV-1 Integrase Inhibitors." Archiv der Pharmazie 335, no. 6 (August 2002): 277. http://dx.doi.org/10.1002/1521-4184(200208)335:6<277::aid-ardp277>3.0.co;2-a.

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18

Vivarini, Bianca Cristina Duarte, and Aislan de Carvalho Vivarini. "Construction and validation of a plasmid for HIV-1 phenotyping assays using Luminescence." Revista Eletrônica Acervo Saúde 13, no. 4 (April 24, 2021): e7209. http://dx.doi.org/10.25248/reas.e7209.2021.

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Objective: The objective of these studies was the construction of a recombination vector for HIV-1 Integrase containing luciferase reporter gene, for the generation of recombinant viruses that can be used in phenotyping assays with integrase inhibitors. Methods: In this work, the vector pNL4-3Luc was molecularly manipulated in order to delete the integrase gene and build a vector for recombination of integrases from different virus subtypes. Results: As a result, viruses with recombinant integrases were generated in HEK293T cells transfected with plasmids, showing significant levels of luminescence. After the purification of the produced viral particles, susceptible lymphocytes were infected with the viruses containing the recombinant integrases and luminescence was detected in both integrases from HIV-1 subtype B and subtype C. Conclusion: The observation of light emission from cells infected by viruses with different integrases can be an efficient method to assess the susceptibility of these viruses in the presence of specific inhibitors for HIV-1 Integrase.

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19

Robinson, W. E., M. G. Reinecke, S. Abdel-Malek, Q. Jia, and S. A. Chow. "Inhibitors of HIV-1 replication that inhibit HIV integrase." Proceedings of the National Academy of Sciences 93, no. 13 (June 25, 1996): 6326–31. http://dx.doi.org/10.1073/pnas.93.13.6326.

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20

Shimura, Kazuya, and Eiichi N. Kodama. "Elvitegravir: A New HIV Integrase Inhibitor." Antiviral Chemistry and Chemotherapy 20, no. 2 (October 2009): 79–85. http://dx.doi.org/10.3851/imp1397.

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Integration is a distinctive and essential process in the HIV infection cycle and thus represents an attractive antiviral drug target. Integrase inhibitors combined with other classes of drug might contribute to long-lasting suppression of HIV type-1 (HIV-1) replication for many patients. Of the numerous potential integrase inhibitor leads that have been reported, few have reached clinical trials and only one, raltegravir, has been approved (in late 2007) for the treatment of HIV-1-infected patients. Another integrase inhibitor, elvitegravir, is currently showing promise in Phase III clinical studies. Once-daily administration of elvitegravir has a comparable antiviral activity to twice-daily of raltegravir in HIV-1-infected patients. Here, we highlight the salient features of elvitegravir: its chemical structure compared with representative integrase inhibitors, mechanism of action, in vitro and in vivo activity against HIV and other retroviruses, and the effect of integrase polymorphisms and resistance mutations on its anti-HIV activity.

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21

Zhang, Chao, Qian Xie, Chi Cheong Wan, Zhe Jin, and Chun Hu. "Recent Advances in Small-Molecule HIV-1 Integrase Inhibitors." Current Medicinal Chemistry 28, no. 24 (August 13, 2021): 4910–34. http://dx.doi.org/10.2174/0929867328666210114124744.

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HIV-1 integrase catalyzed the insertion of viral DNA into the genome of human cells in the process of retrotranscription. Integrase is an attractive target for HIV-1 treatment due to the lack of its homologue in human cells and its vital role in HIV-1 replication. Although major progress in the development of HIV-1 integrase inhibitors has been made, some thorny problems, such as drug resistance, led to the further study of HIV-1 integrase inhibitors. This review briefly discussed the structure, function, and mechanism of catalysis of HIV-1 integrase and made a different conclusion for recent advances in small-molecule inhibitors of HIV-1 integrase.

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22

Kaur, Maninder, Ravindra K. Rawal, Goutam Rath, and Amit K. Goyal. "Structure Based Drug Design: Clinically Relevant HIV-1 Integrase Inhibitors." Current Topics in Medicinal Chemistry 18, no. 31 (February 22, 2019): 2664–80. http://dx.doi.org/10.2174/1568026619666190119143239.

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HIV-1 integrase, a member of a polynucleotidyl transferases superfamily, catalyzes the insertion of the viral DNA into the genome of host cells. It has emerged as a potential target for developing anti-HIV agents. In the last two decades, a number of integrase inhibitors have been developed as potential anti-HIV therapeutics. Several integrase inhibitors have reached later stages of clinical trials including S-1360, L870,810, L870,812 and BMS-707035. Into the bargain, Raltegravir, Elvitegravir and Dolutegravir have been approved by FDA as anti-HIV agents. This review article summarizes the structural insights required for the inhibition of the HIV1 integrase in the context of clinically relevant HIV1 integrase inhibitors. Additionally, the structural features required for overcoming HIV resistance have been discussed. These insights will update the ongoing design of novel antiviral inhibitors.

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23

Radhika, V., S. Sree Kanth, and M. Vijjulatha. "CoMFA and CoMSIA Studies on Inhibitors of HIV-1 Integrase - Bicyclic Pyrimidinones." E-Journal of Chemistry 7, s1 (2010): S75—S84. http://dx.doi.org/10.1155/2010/717865.

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To understand the structural requirements of HIV-1 integrase inhibitors and to design new ligands against human HIV-1 integrase with enhanced inhibitory potency, a 3D QSAR (quantitative structure-activity relationship) study with comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) for a dataset of 35 bicyclic pyrimidinones which are inhibitors of human HIV-1 integrase was performed. QSAR models were computed with Sybyl. The 3D QSAR model showed very good statistical result, namely q2, r2and r2predvalues were high for both CoMFA and CoMSIA. Based on the high values for q2and r2we are confident that the 3D QSAR model gives good predictions that may be used to design better HIV-1 integrase inhibitors. The CoMFA and CoMSIA models reveal that steric and electrostatic fields contribute significantly with biological activities of the studied compounds.

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24

Monforte, Pietro, Stefania Ferro, Angela Rao, Maria Zappalà, Alba Chimirri, Maria Letizia Barreca, Myriam Witvrouw, and Zeger Debyser. "Synthesis of New Potential HIV-1 Integrase Inhibitors." HETEROCYCLES 63, no. 12 (2004): 2727. http://dx.doi.org/10.3987/com-04-10193.

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25

Czyz, Agata, Kara A. Stillmock, Daria J. Hazuda, and William S. Reznikoff. "Dissecting Tn5Transposition Using HIV-1 Integrase Diketoacid Inhibitors†." Biochemistry 46, no. 38 (September 2007): 10776–89. http://dx.doi.org/10.1021/bi7006542.

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26

Depatureaux, Agnès, Thibault Mesplède, Peter Quashie, Maureen Oliveira, Daniela Moisi, Jean-Christophe Plantier, Bluma Brenner, and Mark A. Wainberg. "HIV-1 Group O Resistance Against Integrase Inhibitors." JAIDS Journal of Acquired Immune Deficiency Syndromes 70, no. 1 (September 2015): 9–15. http://dx.doi.org/10.1097/qai.0000000000000698.

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27

Patel, Pratiq A., Nina Kvaratskhelia, Yara Mansour, Janet Antwi, Lei Feng, Pratibha Koneru, Mathew J. Kobe, et al. "Indole-based allosteric inhibitors of HIV-1 integrase." Bioorganic & Medicinal Chemistry Letters 26, no. 19 (October 2016): 4748–52. http://dx.doi.org/10.1016/j.bmcl.2016.08.037.

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28

Dayam, Raveendra, Laith Q. Al-Mawsawi, and Nouri Neamati. "Substituted 2-pyrrolinone inhibitors of HIV-1 integrase." Bioorganic & Medicinal Chemistry Letters 17, no. 22 (November 2007): 6155–59. http://dx.doi.org/10.1016/j.bmcl.2007.09.061.

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29

Malet, Isabelle, Vincent Calvez, and Anne-Geneviève Marcelin. "The future of integrase inhibitors of HIV-1." Current Opinion in Virology 2, no. 5 (October 2012): 580–87. http://dx.doi.org/10.1016/j.coviro.2012.08.005.

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30

Neamati, Nouri, Sanjay Sunder, and Yves Pommier. "Design and discovery of HIV-1 integrase inhibitors." Drug Discovery Today 2, no. 11 (November 1997): 487–98. http://dx.doi.org/10.1016/s1359-6446(97)01105-7.

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31

Makhija, Mahindra T., and Vithal M. Kulkarni. "Eigen Value Analysis of HIV-1 Integrase Inhibitors." Journal of Chemical Information and Computer Sciences 41, no. 6 (October 5, 2001): 1569–77. http://dx.doi.org/10.1021/ci0001334.

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32

Olomola, Temitope O., Salerwe Mosebi, Rosalyn Klein, Telisha Traut-Johnstone, Judy Coates, Raymond Hewer, and Perry T. Kaye. "Novel furocoumarins as potential HIV-1 integrase inhibitors." Bioorganic Chemistry 57 (December 2014): 1–4. http://dx.doi.org/10.1016/j.bioorg.2014.07.008.

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33

Ramcharan, Joseph, and Anna Marie Skalka. "Strategies for identification of HIV-1 integrase inhibitors." Future Virology 1, no. 6 (November 2006): 717–31. http://dx.doi.org/10.2217/17460794.1.6.717.

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34

Lin, Zhaiwei, Nouri Neamati, He Zhao, Yoshimitsu Kiryu, Jim A. Turpin, Claudia Aberham, Klaus Strebel, et al. "Chicoric Acid Analogues as HIV-1 Integrase Inhibitors." Journal of Medicinal Chemistry 42, no. 8 (April 1999): 1401–14. http://dx.doi.org/10.1021/jm980531m.

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35

Deng, Jinxia, Raveendra Dayam, Laith Al-Mawsawi, and Nouri Neamati. "Design of Second Generation HIV-1 Integrase Inhibitors." Current Pharmaceutical Design 13, no. 2 (January 1, 2007): 129–41. http://dx.doi.org/10.2174/138161207779313687.

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36

Li, Yang, Shouyi Xuan, Yue Feng, and Aixia Yan. "Targeting HIV-1 integrase with strand transfer inhibitors." Drug Discovery Today 20, no. 4 (April 2015): 435–49. http://dx.doi.org/10.1016/j.drudis.2014.12.001.

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37

Foster, Emma G., Howard E. Gendelman, and Aditya N. Bade. "HIV-1 Integrase Strand Transfer Inhibitors and Neurodevelopment." Pharmaceuticals 15, no. 12 (December 9, 2022): 1533. http://dx.doi.org/10.3390/ph15121533.

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Children born to mothers, with or at risk, of human immunodeficiency virus type-1 (HIV-1) infection are on the rise due to affordable access of antiretroviral therapy (ART) to pregnant women or those of childbearing age. Each year, up to 1.3 million HIV-1-infected women on ART have given birth with recorded mother-to-child HIV-1 transmission rates of less than 1%. Despite this benefit, the outcomes of children exposed to antiretroviral drugs during pregnancy, especially pre- and post- natal neurodevelopment remain incompletely understood. This is due, in part, to the fact that pregnant women are underrepresented in clinical trials. This is underscored by any potential risks of neural tube defects (NTDs) linked, in measure, to periconceptional usage of dolutegravir (DTG). A potential association between DTG and NTDs was first described in Botswana in 2018. Incidence studies of neurodevelopmental outcomes associated with DTG, and other integrase strand transfer inhibitors (INSTIs) are limited as widespread use of INSTIs has begun only recently in pregnant women. Therefore, any associations between INSTI use during pregnancy, and neurodevelopmental abnormalities remain to be explored. Herein, United States Food and Drug Administration approved ARVs and their use during pregnancy are discussed. We provide updates on INSTI pharmacokinetics and adverse events during pregnancy together with underlying mechanisms which could affect fetal neurodevelopment. Overall, this review seeks to educate both clinical and basic scientists on potential consequences of INSTIs on fetal outcomes as a foundation for future scientific investigations.

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38

Korolev, S. P., M. A. Pustovarova, A. M. Starosotnikov, M. A. Bastrakov, Yu Yu Agapkina, S. A. Shevelev, and M. B. Gottikh. "Nitrobenzofuroxane derivatives as dual action HIV-1 inhibitors." Biomeditsinskaya Khimiya 62, no. 6 (2016): 725–28. http://dx.doi.org/10.18097/pbmc20166206725.

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Human immunodeficiency virus first type (HIV-1) is a main cause of one of the most dangerous diseases, AIDS. The search for new inhibitors of the virus still remains an urgent task. One approach to suppress the HIV infection is to use a double-acting inhibitors, i.e. inhibitors directed to two stages of the viral life cycle. The catalytic domain of HIV-1 integrase has a similar spatial organization with ribonuclease (RNase H) domain of HIV-1 reverse transcriptase, and approach aimed to create HIV-1 integrase and RNase H double-acting is very promising. In this work we synthesized a series of 6-nitrobenzofuroxane derivatives and studied their ability to inhibit two viral enzymes – integrase and RNase H HIV-1.

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39

Ason, Brandon, Daniel J. Knauss, Allison M. Balke, George Merkel, Anna Marie Skalka, and William S. Reznikoff. "Targeting Tn5 Transposase Identifies Human Immunodeficiency Virus Type 1 Inhibitors." Antimicrobial Agents and Chemotherapy 49, no. 5 (May 2005): 2035–43. http://dx.doi.org/10.1128/aac.49.5.2035-2043.2005.

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ABSTRACT Human immunodeficiency virus (HIV) type 1 (HIV-1) integrase is an underutilized drug target for the treatment of HIV infection. One limiting factor is the lack of costructural data for use in the rational design or modification of integrase inhibitors. Tn5 transposase is a structurally well characterized, related protein that may serve as a useful surrogate. However, little data exist on inhibitor cross-reactivity. Here we screened 16,000 compounds using Tn5 transposase as the target and identified 20 compounds that appear to specifically inhibit complex assembly. Six were found to also inhibit HIV-1 integrase. These compounds likely interact with a highly conserved region presumably within the catalytic core. Most promising, several cinnamoyl derivatives were found to inhibit HIV transduction in cells. The identification of integrase inhibitors from a screen using Tn5 transposase as the target illustrates the utility of Tn5 as a surrogate for HIV-1 integration even though the relationship between the two systems is limited to the active site architecture and catalytic mechanism.

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40

Ingale, Kundan B., and Manish S. Bhatia. "HIV-1 Integrase Inhibitors: A Review of Their Chemical Development." Antiviral Chemistry and Chemotherapy 22, no. 3 (January 1, 2011): 95–105. http://dx.doi.org/10.3851/imp1740.

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Highly active antiretroviral therapy (HAART) significantly decreases plasma viral load, increases CD4+ T-cell counts in HIV-1-infected patients and has reduced progression to AIDS in developed countries. However, adverse side effects, and emergence of drug resistance, mean there is still a demand for new anti-HIV agents. The HIV integrase (IN) is a target that has been the focus of rational drug design over the past decade. In 2007, raltegravir was the first IN inhibitor approved by the US Food and Drug Administration for antiretroviral combination therapy, while another IN inhibitor, elvitegravir, is currently in Phase III clinical trials. This article reviews the development and resistance profiling of small molecule HIV-1 IN inhibitors.

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41

Ni, Xiaoju, Safwat Abdel-Azeim, Elodie Laine, Rohit Arora, Osamuede Osemwota, Anne-Geneviève Marcelin, Vincent Calvez, Jean-François Mouscadet, and Luba Tchertanov. "In SilicoandIn VitroComparison of HIV-1 Subtypes B and CRF02_AG Integrases Susceptibility to Integrase Strand Transfer Inhibitors." Advances in Virology 2012 (2012): 1–13. http://dx.doi.org/10.1155/2012/548657.

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Most antiretroviral medical treatments were developed and tested principally on HIV-1 B nonrecombinant strain, which represents less than 10% of the worldwide HIV-1-infected population. HIV-1 circulating recombinant form CRF02_AG is prevalent in West Africa and is becoming more frequent in other countries. Previous studies suggested that the HIV-1 polymorphisms might be associated to variable susceptibility to antiretrovirals. This study is pointed to compare the susceptibility to integrase (IN) inhibitors of HIV-1 subtype CRF02_AG IN respectively to HIV-1 B. Structural models of B and CRF02_AG HIV-1 INs as unbound enzymes and in complex with the DNA substrate were built by homology modeling. IN inhibitors—raltegravir (RAL), elvitegravir (ELV) and L731,988—were docked onto the models, and their binding affinity for both HIV-1 B and CRF02_AG INs was compared. CRF02_AG INs were cloned and expressed from plasma of integrase strand transfer inhibitor (INSTI)-naïve infected patients. Ourin silicoandin vitrostudies showed that the sequence variations between the INs of CRF02_AG and B strains did not lead to any notable difference in the structural features of the enzyme and did not impact the susceptibility to the IN inhibitors. The binding modes and affinities of INSTI inhibitors to B and CRF02_AG INs were found to be similar. Although previous studies suggested that several naturally occurring variations of CRF02_AG IN might alter either IN/vDNA interactions or INSTIs binding, our study demonstrate that these variations do affect neither IN activity nor its susceptibility to INSTIs.

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42

Korolev, S. P., T. S. Zatsepin, and M. B. Gottikh. "Oligonucleotide inhibitors of HIV-1 integrase efficiently inhibit HIV-1 reverse transcriptase." Russian Journal of Bioorganic Chemistry 43, no. 2 (March 2017): 135–39. http://dx.doi.org/10.1134/s1068162017020078.

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43

Myers, Richard E., and Deenan Pillay. "Analysis of Natural Sequence Variation and Covariation in Human Immunodeficiency Virus Type 1 Integrase." Journal of Virology 82, no. 18 (July 2, 2008): 9228–35. http://dx.doi.org/10.1128/jvi.01535-07.

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ABSTRACT Human immunodeficiency virus type 1 (HIV-1) integrase inhibitors are in clinical trials, and raltegravir and elvitegravir are likely to be the first licensed drugs of this novel class of HIV antivirals. Understanding resistance to these inhibitors is important to maximize their efficacy. It has been shown that natural variation and covariation provide valuable insights into the development of resistance for established HIV inhibitors. Therefore, we have undertaken a study to fully characterize natural polymorphisms and amino acid covariation within an inhibitor-naïve sequence set spanning all defined HIV-1 subtypes. Inter- and intrasubtype variation was greatest in a 50-amino-acid segment of HIV-1 integrase incorporating the catalytic aspartic acid codon 116, suggesting that polymorphisms affect inhibitor binding and pathways to resistance. The critical mutations that determine the resistance pathways to raltegravir and elvitegravir (N155H, Q148K/R/H, and E92Q) were either rare or absent from the 1,165-sequence data set. However, 25 out of 41 mutations associated with integrase inhibitor resistance were present. These mutations were not subtype associated and were more prevalent in the subtypes that had been sampled frequently within the database. A novel modification of the Jaccard index was used to analyze amino acid covariation within HIV-1 integrase. A network of 10 covarying resistance-associated mutations was elucidated, along with a further 15 previously undescribed mutations that covaried with at least two of the resistance positions. The validation of covariation as a predictive tool will be dependent on monitoring the evolution of HIV-1 integrase under drug selection pressure.

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Farnet, C. M., B. Wang, M. Hansen, J. R. Lipford, L. Zalkow, W. E. Robinson, J. Siegel, and F. Bushman. "Human Immunodeficiency Virus Type 1 cDNA Integration: New Aromatic Hydroxylated Inhibitors and Studies of the Inhibition Mechanism." Antimicrobial Agents and Chemotherapy 42, no. 9 (September 1, 1998): 2245–53. http://dx.doi.org/10.1128/aac.42.9.2245.

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ABSTRACT Integration of the human immunodeficiency virus type 1 (HIV-1) cDNA is a required step for viral replication. Integrase, the virus-encoded enzyme important for integration, has not yet been exploited as a target for clinically useful inhibitors. Here we report on the identification of new polyhydroxylated aromatic inhibitors of integrase including ellagic acid, purpurogallin, 4,8,12-trioxatricornan, and hypericin, the last of which is known to inhibit viral replication. These compounds and others were characterized in assays with subviral preintegration complexes (PICs) isolated from HIV-1-infected cells. Hypericin was found to inhibit PIC assays, while the other compounds tested were inactive. Counterscreening of these and other integrase inhibitors against additional DNA-modifying enzymes revealed that none of the polyhydroxylated aromatic compounds are active against enzymes that do not require metals (methylases, a pox virus topoisomerase). However, all were cross-reactive with metal-requiring enzymes (restriction enzymes, a reverse transcriptase), implicating metal atoms in the inhibitory mechanism. In mechanistic studies, we localized binding of some inhibitors to the catalytic domain of integrase by assaying competition of binding by labeled nucleotides. These findings help elucidate the mechanism of action of the polyhydroxylated aromatic inhibitors and provide practical guidance for further inhibitor development.

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Hearps, Anna C., Vicki Greengrass, Jennifer Hoy, and Suzanne M. Crowe. "An HIV-1 integrase genotype assay for the detection of drug resistance mutations." Sexual Health 6, no. 4 (2009): 305. http://dx.doi.org/10.1071/sh09041.

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Background: The integrase inhibitors (e.g. Raltegravir) are a new class of antiretroviral drugs that have recently become available for the treatment of patients with multi-drug resistant HIV-1 within Australia. The emergence of mutations that confer resistance to the integrase inhibitors has been observed in vivo; however, no commercial genotyping assay is currently available to screen for resistance to these drugs. Methods: The HIV-1 integrase gene was amplified from plasma-derived HIV-1 viral RNA via reverse transcription-polymerase chain reaction and genotype determined via population DNA sequencing. Drug resistance mutations and polymorphisms were detected using the Stanford University online HIV database. Assay sensitivity and reproducibility were determined using clinical and laboratory-derived samples. Results: Our in-house assay was capable of genotyping the integrase gene from all samples tested (n = 30) of HIV-1 subtypes B, C, D, F, CFR01_AE and CRF02_AG and can amplify the integrase region from plasma samples containing as few as 50 HIV RNA copies/mL. The assay is highly reproducible (average nucleotide concordance = 99.6%, n = 4) and is capable of detecting resistance-associated mutations. Conclusions:This assay is suitable for routine drug resistance screening of plasma samples from HIV-infected patients receiving integrase inhibitor antiretroviral drugs and also serves as a useful research tool.

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Dinh, Long Phi, Jian Sun, Courtney D. Glenn, Krunal Patel, Julie A. Pigza, Matthew G. Donahue, Larry Yet, and Jacques J. Kessl. "Multi-Substituted Quinolines as HIV-1 Integrase Allosteric Inhibitors." Viruses 14, no. 7 (July 2, 2022): 1466. http://dx.doi.org/10.3390/v14071466.

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Allosteric HIV-1 integrase (IN) inhibitors, or ALLINIs, are a new class of antiviral agents that bind at the dimer interface of the IN, away from the enzymatic catalytic site and block viral replication by triggering an aberrant multimerization of the viral enzyme. To further our understanding of the important binding features of multi-substituted quinoline-based ALLINIs, we have examined the IN multimerization and antiviral properties of substitution patterns at the 6 or 8 position. We found that the binding properties of these ALLINIs are negatively impacted by the presence of bulky substitutions at these positions. In addition, we have observed that the addition of bromine at either the 6 (6-bromo) or 8 (8-bromo) position conferred better antiviral properties. Finally, we found a significant loss of potency with the 6-bromo when tested with the ALLINI-resistant IN A128T mutant virus, while the 8-bromo analog retained full effectiveness.

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Nunthaboot, Nadtanet, Somsak Pianwanit, Vudhichai Parasuk, Sirirat Kokpol, and James Briggs. "Computational Studies of HIV-1 Integrase and its Inhibitors." Current Computer Aided-Drug Design 3, no. 3 (September 1, 2007): 160–90. http://dx.doi.org/10.2174/157340907781695459.

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Sotriffer, Christoph A., Ni, and J. Andrew McCammon. "Active Site Binding Modes of HIV-1 Integrase Inhibitors." Journal of Medicinal Chemistry 43, no. 22 (November 2000): 4109–17. http://dx.doi.org/10.1021/jm000194t.

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Sato, Motohide, Takahisa Motomura, Hisateru Aramaki, Takashi Matsuda, Masaki Yamashita, Yoshiharu Ito, Hiroshi Kawakami, et al. "Novel HIV-1 Integrase Inhibitors Derived from Quinolone Antibiotics." Journal of Medicinal Chemistry 49, no. 5 (March 2006): 1506–8. http://dx.doi.org/10.1021/jm0600139.

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Plewe, Michael B., Scott L. Butler, Klaus R. Dress, Qiyue Hu, Ted W. Johnson, Jon E. Kuehler, Atsuo Kuki, et al. "Azaindole Hydroxamic Acids are Potent HIV-1 Integrase Inhibitors." Journal of Medicinal Chemistry 52, no. 22 (November 26, 2009): 7211–19. http://dx.doi.org/10.1021/jm900862n.

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Journal articles on the topic 'HIV-1 Integrase Inhibitors'

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