Resistance to HIV integrase strand transfer inhibitors: in vitro findings and clinical consequences

2014 ◽  
Vol 8 ◽  
pp. 98-103 ◽  
Author(s):  
Jay A. Grobler ◽  
Daria J. Hazuda
Keyword(s):  
Strand Transfer ◽  
Hiv Integrase ◽  
Integrase Strand Transfer Inhibitors ◽  
Clinical Consequences

Design, Synthesis and In Vitro Evaluation of 4-Oxo-6-Substituted Phenyl- 2-Thioxo1,2,3,4-Tetrahydropyrimidine-5-Carbonitrile Derivatives as HIV Integrase Strand Transfer Inhibitors

2020 ◽  
Vol 17 ◽  
Author(s):  
Pankaj Wadhwa ◽  
Priti Jain ◽  
Hemant R. Jadhav
Keyword(s):  
In Silico ◽  
Strand Transfer ◽  
Hiv Integrase ◽  
Chromosomal Dna ◽  
Molecular Docking Study ◽  
Design Synthesis ◽  
In Vitro Evaluation ◽  
Integrase Strand Transfer Inhibitors ◽  
Hiv 1

Aim:: To design, synthesis and in vitro evaluation of 4-oxo-6-substituted phenyl-2-thioxo1,2,3,4- tetrahydropyrimidine-5-carbonitrile derivatives as HIV integrase strand transfer inhibitors. Background:: Human immunodeficiency virus-1 (HIV-1), a member of retroviridae family, is the primary causative agent of acquired immunodeficiency syndrome (AIDS). Three enzymes viz: integrase (IN), reverse transcriptase (RT) and protease play important role in its replication cycle. HIV-1 integrase is responsible for the incorporation of viral DNA into human chromosomal DNA by catalyzing two independent reactions, 3′-processing (3′-P) and strand transfer (ST), which are observed as the “point of no-return” in HIV infection. Objective:: To develop inhibitors against HIV integrase strand transfer step. Methods:: Our previous results indicated that tetrahydro pyrimidine-5-carboxamide derivatives are potent HIV-1 IN inhibitors (unpublished results from our laboratory). Taking clue from above studies and our own experience, we hypothesized 4- oxo-6-substituted phenyl-2-thioxo1,2,3,4-tetrahydropyrimidine-5-carbonitrile analogues (14a to 14n) as inhibitors of HIV-1 Integrase strand transfer. As shown in figure 2, prototype compound 14 can be viewed as hybrid structure having characteristics of dihydropyrimidine derivatives 10-12 and tyrphostin 13. Result:: A total of fourteen derivatives of 4-oxo-6-substituted phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (14a-14n) were synthesized and evaluated using HIV-1 Integrase Assay Kit (Xpressbio Life Science Products, USA). The percentage inhibition of all compounds was investigated at 10 μM concentration and IC50 value of few highly active compounds was studied. The obtained results were validated by in silico molecular docking study using Glide (maestro version 9.3, Schrödinger suite) in extra precision (XP) mode. Conclusion:: Fourteen 4-oxo-6-substituted phenyl-2-thioxo 1,2,3,4-tetrahydropyrimidine-5-carbonitrile analogues were synthesized and evaluated for HIV-1 IN inhibitory activity. Three compounds 14a, 14e, and 14h exhibited significant percentage inhibition of HIV-1 IN. There was good in vitro - in silico correlation. However, none of the derivative was active against HIV-1 and HIV-2 below their cytotoxic concentration. It needs to be seen whether these compounds can be explored further for their anti-HIV or cytotoxic potential.

scholarly journals Systematic determination of in vitro phenotypic resistance to HIV-1 integrase strand transfer inhibitors from clinical samples

2019 ◽  
Author(s):  
Aniqa Shahid ◽  
Wendy W. Zhang ◽  
Vincent Montoya ◽  
Peter K. Cheung ◽  
Natalia Oliveira ◽  
...  
Keyword(s):  
Site Directed Mutagenesis ◽  
Cross Resistance ◽  
Clinical Samples ◽  
Strand Transfer ◽  
Hiv Integrase ◽  
Phenotypic Resistance ◽  
Integrase Strand Transfer Inhibitors ◽  
Hiv 1

ABSTRACTPhenotypic resistance data is relatively sparse for the newest HIV-1 integrase strand transfer inhibitors (INSTIs), dolutegravir (DTG), bictegravir (BIC), and cabotegravir (CAB). In this study, we report the phenotypic susceptibility of a large panel of oligo-clonal patient-derived HIV-1 integrase viruses. Representative clinical samples (N=141) were selected from a large database (N=17,197) of clinically-derived HIV integrase sequences, based on the presence of permutations of substitutions at 27 pre-defined positions in integrase (N=288). HIV-1 RNA was extracted from patient samples and diluted to approximately 500 HIV RNA copies/mL. Using an “oligo-clonal” amplification approach to achieve single-copy amplification, these dilutions were subjected to 12 parallel RT-PCR reactions to amplify integrase. Confirmed clonal amplicons were co-transfected with linearized pNL4.3∆int into CEM-GXR cells. In total, 162 HIV-1 viruses that carried no mixtures and had a unique sequence were harvested, and phenotyped in MT4-LTR-EGFP cells subsequently. Variants with the highest fold change (FC) had G140S and Q148R/H and resistant to all five drugs; R263K was the only single variant conferring >3-FC to DTG, BIC and CAB. There was extensive cross-resistance between DTG, BIC, and CAB and phenotypic resistance values for all the three INSTIs were almost collinear. The greatest exceptions were variants with N155H/G163E or L74I/T97M/F121C/V151I/E157Q/G163K, where both had >70-FC for CAB, while <3-FC for DTG and BIC. While site-directed mutagenesis is invaluable; the systematic selection of representative mutational patterns observedin vivoprovides an efficient way to identify clinically relevant drug resistance.

Synthesis and Evaluation of 3-(1,3-dioxoisoindolin-2-yl)-N-substituted Phenyl Benzamide Analogues as HIV Integrase Strand Transfer Inhibitors

2019 ◽  
Vol 17 (2) ◽  
pp. 105-114
Author(s):  
Pankaj Wadhwa ◽  
Priti Jain ◽  
Arpit Patel ◽  
Shantanu Shinde ◽  
Hemant R. Jadhav
Keyword(s):  
Structural Features ◽  
Docking Studies ◽  
Significant Inhibition ◽  
Strand Transfer ◽  
Hiv Integrase ◽  
In Silico Docking ◽  
Immunodeficiency Virus ◽  
Hiv 1

<P>Background: A series of novel 3-(1,3-dioxoisoindolin-2-yl)-N-substituted phenyl benzamide derivatives was synthesized and tested in vitro against human immunodeficiency virus type-1 Integrase (HIV-1 IN). Methods: Out of the 18 analogues, six (compounds 16c, 16h, 16i, 16m, 16n and 16r) showed significant inhibition of strand transfer by HIV-1 integrase. For these six compounds. IC50 was below 5.0 µM. In silico docking studies revealed that the presence of 2-phenyl isoindoline-1,3-dione motif was essential as it was found to interact with active site magnesium. Results: To further confirm the results, cell-based HIV-1 and HIV-2 inhibitory assay was carried out. Conclusion: These compounds possess structural features not seen in previously reported HIV-1 integrase inhibitors and thus can help further optimization of anti-HIV-1 integrase activity.</P>

scholarly journals The Terminal (Catalytic) Adenosine of the HIV LTR Controls the Kinetics of Binding and Dissociation of HIV Integrase Strand Transfer Inhibitors

Biochemistry ◽  
2008 ◽  
Vol 47 (51) ◽  
pp. 13481-13488 ◽  
Author(s):  
David R. Langley ◽  
Himadri K. Samanta ◽  
Zeyu Lin ◽  
Michael A. Walker ◽  
Mark R. Krystal ◽  
...  
Keyword(s):  
Strand Transfer ◽  
Hiv Integrase ◽  
Integrase Strand Transfer Inhibitors ◽  
Kinetics Of

scholarly journals Antiviral Characteristics of GSK1265744, an HIV Integrase Inhibitor Dosed Orally or by Long-Acting Injection

2014 ◽  
Vol 59 (1) ◽  
pp. 397-406 ◽  
Author(s):  
Tomokazu Yoshinaga ◽  
Masanori Kobayashi ◽  
Takahiro Seki ◽  
Shigeru Miki ◽  
Chiaki Wakasa-Morimoto ◽  
...  
Keyword(s):  
Synergistic Effects ◽  
Integrase Inhibitor ◽  
Culture Conditions ◽  
Strand Transfer ◽  
Hiv Integrase ◽  
Hiv Replication ◽  
Data Set ◽  
Long Acting ◽  
Anti Hiv

ABSTRACTGSK1265744 is a new HIV integrase strand transfer inhibitor (INSTI) engineered to deliver efficient antiviral activity with a once-daily, low-milligram dose that does not require a pharmacokinetic booster. Thein vitroantiviral profile and mechanism of action of GSK1265744 were established through integrase enzyme assays, resistance passage experiments, and cellular assays with site-directed molecular (SDM) HIV clones resistant to other classes of anti-HIV-1 agents and earlier INSTIs. GSK1265744 inhibited HIV replication with low or subnanomolar efficacy and with a selectivity index of at least 22,000 under the same culture conditions. The protein-adjusted half-maximal inhibitory concentration (PA-EC50) extrapolated to 100% human serum was 102 nM. When the virus was passaged in the presence of GSK1265744, highly resistant mutants with more than a 10-fold change (FC) in EC50relative to that of the wild-type were not observed for up to 112 days of culture. GSK1265744 demonstrated activity against SDM clones containing the raltegravir (RAL)-resistant Y143R, Q148K, N155H, and G140S/Q148H signature variants (FC less than 6.1), while these mutants had a high FC in the EC50for RAL (11 to >130). Either additive or synergistic effects were observed when GSK1265744 was tested in combination with representative anti-HIV agents, and no antagonistic effects were seen. These findings demonstrate that, similar to dolutegravir, GSK1265744 is differentiated as a new INSTI, having a markedly distinct resistance profile compared with earlier INSTIs, RAL, and elvitegravir (EVG). The collective data set supports further clinical development of GSK1265744.

Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide discontinuation and return to normal weight

2020 ◽  
pp. 095646242096434 ◽  
Author(s):  
Blake Max ◽  
Patricia DeMarais
Keyword(s):  
Weight Gain ◽  
Normal Weight ◽  
Strand Transfer ◽  
Hiv Integrase ◽  
Combination Antiretroviral Therapy ◽  
Excessive Weight ◽  
Integrase Strand Transfer Inhibitors ◽  
Baseline Weight ◽  
Tenofovir Alafenamide

HIV integrase strand transfer inhibitors (INSTI) are considered well tolerated with few treatment-limiting adverse effects. However, emerging data from clinical trials has identified excessive weight gain possibly due to INSTI alone or with tenofovir alafenamide as a new and possible long-term complication of combination antiretroviral therapy (cART). Identifying who is at greatest risk and whether the unintended weight gain is reversible remain unanswered questions. We report a return to baseline weight after switching back to tenofovir disoproxil/emtricitabine/efavirenz (Atripla®) in a woman who had profound weight gain due to tenofovir alafenamide/emtricitabine/cobicistat/elvitegravir (Genvoya®).

Quinoline-based Protein–protein Interaction Inhibitors of LEDGF/p75 and HIV Integrase: An In Silico Study

2019 ◽  
Vol 18 (32) ◽  
pp. 2800-2815 ◽  
Author(s):  
Nisha Chhokar ◽  
Sourav Kalra ◽  
Monika Chauhan ◽  
Anjana Munshi ◽  
Raj Kumar
Keyword(s):  
Protein Interactions ◽  
Biological Data ◽  
Strand Transfer ◽  
Hiv Integrase ◽  
Protein Protein Interactions ◽  
Allosteric Site ◽  
Protein Protein Interaction ◽  
In Silico Study ◽  
Cellular Cofactor

The failure of the Integrase Strand Transfer Inhibitors (INSTIs) due to the mutations occurring at the catalytic site of HIV integrase (IN) has led to the design of allosteric integrase inhibitors (ALLINIs). Lens epithelium derived growth factor (LEDGF/p75) is the host cellular cofactor which helps chaining IN to the chromatin. The protein-protein interactions (PPIs) were observed at the allosteric site (LEDGF/p75 binding domain) between LEDGF/p75 of the host cell and IN of virus. In recent years, many small molecules such as CX04328, CHIBA-3053 and CHI-104 have been reported as LEDGF/p75-IN interaction inhibitors (LEDGINs). LEDGINs have emerged as promising therapeutics to halt the PPIs by binding at the interface of both the proteins. In the present work, we correlated the docking scores for the reported LEDGINs containing quinoline scaffold with the in vitro biological data. The hierarchal clustering method was used to divide the compounds into test and training set. The robustness of the generated model was validated by q2 and r2 for the predicted set of compounds. The generated model between the docking score and biological data was assessed to predict the activity of the hits (quinoline scaffold) obtained from virtual screening of LEDGINs providing their structureactivity relationships to aim for the generation of potent agents.

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