scholarly journals Discovery of a Potent HIV Integrase Inhibitor That Leads to a Prodrug with Significant anti-HIV Activity

2011 ◽  
Vol 2 (12) ◽  
pp. 877-881 ◽  
Author(s):  
Byung I. Seo ◽  
Vinod R. Uchil ◽  
Maurice Okello ◽  
Sanjay Mishra ◽  
Xiao-Hui Ma ◽  
...  
Keyword(s):  
Integrase Inhibitor ◽  
Hiv Integrase ◽  
Anti Hiv

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.

scholarly journals Structural basis of second-generation HIV integrase inhibitor action and viral resistance

Science ◽  
2020 ◽  
Vol 367 (6479) ◽  
pp. 806-810 ◽  
Author(s):  
Nicola J. Cook ◽  
Wen Li ◽  
Dénes Berta ◽  
Magd Badaoui ◽  
Allison Ballandras-Colas ◽  
...  
Keyword(s):  
Second Generation ◽  
Integrase Inhibitor ◽  
Structural Basis ◽  
Strand Transfer ◽  
Hiv Integrase ◽  
Enzyme Active Site ◽  
Structural Framework ◽  
Cryo Electron Microscopy ◽  
Mechanistic Basis ◽  
Anti Hiv

Although second-generation HIV integrase strand-transfer inhibitors (INSTIs) are prescribed throughout the world, the mechanistic basis for the superiority of these drugs is poorly understood. We used single-particle cryo–electron microscopy to visualize the mode of action of the advanced INSTIs dolutegravir and bictegravir at near-atomic resolution. Glutamine-148→histidine (Q148H) and glycine-140→serine (G140S) amino acid substitutions in integrase that result in clinical INSTI failure perturb optimal magnesium ion coordination in the enzyme active site. The expanded chemical scaffolds of second-generation compounds mediate interactions with the protein backbone that are critical for antagonizing viruses containing the Q148H and G140S mutations. Our results reveal that binding to magnesium ions underpins a fundamental weakness of the INSTI pharmacophore that is exploited by the virus to engender resistance and provide a structural framework for the development of this class of anti-HIV/AIDS therapeutics.

Novel Second Generation HIV Integrase Inhibitor-DOLUTEGRAVIR: An Emerging Weapon Against HIV

2017 ◽  
Vol 14 (3) ◽  
pp. 354-371 ◽  
Author(s):  
Vivek Jain ◽  
Diksha Gupta ◽  
Ashutosh Pareek ◽  
Yashumati Ratan
Keyword(s):  
Second Generation ◽  
Integrase Inhibitor ◽  
Hiv Integrase

scholarly journals No difference in HIV-1 integrase inhibitor resistance between CSF and blood compartments

2021 ◽  
Author(s):  
Basma Abdi ◽  
Mouna Chebbi ◽  
Marc Wirden ◽  
Elisa Teyssou ◽  
Sophie Sayon ◽  
...  
Keyword(s):  
Integrase Inhibitor ◽  
Routine Care ◽  
Biological Data ◽  
Recombinant Form ◽  
Hiv Integrase ◽  
Resistance Mutations ◽  
Clinical Routine ◽  
Inhibitor Resistance ◽  
Hiv 1

Abstract Background Little is known about HIV-1 integrase inhibitor resistance in the CNS. Objectives This study aimed to evaluate integrase inhibitor resistance in CSF, as a marker of the CNS, and compare it with the resistance in plasma. Methods HIV integrase was sequenced both in plasma and CSF for 59 HIV-1 patients. The clinical and biological data were collected from clinical routine care. Results Among the 59 HIV-1 patients, 32 (54.2%) were under antiretroviral (ARV) treatment. The median (IQR) HIV-1 RNA in the plasma of viraemic patients was 5.32 (3.85–5.80) and 3.59 (2.16–4.50) log10 copies/mL versus 4.79 (3.56–5.25) and 3.80 (2.68–4.33) log10 copies/mL in the CSF of ARV-naive and ARV-treated patients, respectively. The patients were mainly infected with non-B subtypes (72.2%) with the most prevalent recombinant form being CRF02_AG (42.4%). The HIV-1 integrase sequences from CSF presented resistance mutations for 9/27 (33.3%) and 8/32 (25.0%) for ARV-naive (L74I, n = 3; L74I/M, n = 1; T97A, n = 1; E157Q, n = 4) and ARV-treated (L74I, n = 6; L74M, n = 1; T97A, n = 1; N155H, n = 1) patients, respectively. Integrase inhibitor resistance mutations in CSF were similar to those in plasma, except for 1/59 patients. Conclusions This work shows similar integrase inhibitor resistance profiles in the CNS and plasma in a population of HIV-1 viraemic patients.

Design, Synthesis and Anti-HIV Integrase Evaluation of 1,2,3- Triazol-4-yl-substituted 1,4-Dihydro-4-oxo-1,5-napthyridine- 3-carboxylic Acids

2009 ◽  
Vol 27 (5) ◽  
pp. 953-962 ◽  
Author(s):  
Jia ZENG ◽  
Xiuhua LÜ ◽  
Chengchu ZENG ◽  
Liming HU ◽  
Rugang ZHONG
Keyword(s):  
Carboxylic Acids ◽  
Hiv Integrase ◽  
Design Synthesis ◽  
Anti Hiv

Anti-HIV Integrase Inhibitors as New Candidates for the Treatment of COVID-19: A Narrative Literature Review

2021 ◽  
Vol 19 ◽  
Author(s):  
Sofia Salari ◽  
Hedyieh Karbasforooshan ◽  
Hesamoddin Hosseinjani
Keyword(s):  
Treatment Options ◽  
World Health ◽  
Health Concern ◽  
Strand Transfer ◽  
Hiv Integrase ◽  
Integrase Inhibitors ◽  
Curative Therapy ◽  
Narrative Literature Review ◽  
Hiv Drugs ◽  
Anti Hiv

Background: The initial reports of a contagious novel Severe Acute Respiratory Syndrome – Coronavirus-2 (SARS-CoV-2) were proclaimed by Wuhan, Hubei province, China. This pathogen quickly became a health concern due to the World Health Organization's (WHO) alarm of its pandemic essence. Hence, there is an urgent need for efficacious and curative therapy against COVID-19. Objective: Theoretically, repurposing anti-viral drugs, specifically HIV treatments, could help the urgent need for treating COVID-19 due to the structural similarities of their critical enzyme substrates. Integrase inhibitors are a category of anti-HIV drugs that inhibit integrase strand transfer. In this review, we investigate the binding affinity and stability of raltegravir, dolutegravir, bictegravir, and elvitegravir in interactions with crucial enzymes of coronavirus. Methods: A literature search was conducted using scientific databases such as Web of Science, Medline (PubMed), Scopus, Google Scholar, and Embase from commencement to September 2020. The most relevant articles regarding the potential effects of integrase inhibitors against COVID-19 were gathered. Ultimately, ten original articles related to the searched terms were selected for this narrative review. Results: Apparently, in addition to the recent drugs prescribed to cure SARS-CoV-2, integrase inhibitors are promising drugs for repurposing in COVID-19 treatment. Several studies on raltegravir, dolutegravir, bictegravir and elvitegravir were conducted using virtual screening to guess either they are effective or not. Encouraging results were mostly reported for raltegravir and dolutegravir. Nevertheless, bictegravir and elvitegravir need more investigations. Conclusion: Further experimental and clinical studies of antiviral drugs are necessary to introduce appropriate treatment options for COVID-19.

Radiosynthesis of the HIV integrase inhibitor [18F]MK-0518 (Isentress)

2010 ◽  
pp. n/a-n/a ◽  
Author(s):  
Wenping Li ◽  
Wayne Thompson ◽  
Thorsten Fisher ◽  
John S. Wai ◽  
Daria Hazuda ◽  
...  
Keyword(s):  
Integrase Inhibitor ◽  
Hiv Integrase
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