scholarly journals Integrase Inhibitor Prodrugs: Approaches to Enhancing the Anti-HIV Activity of β-Diketo Acids

Molecules ◽  
2015 ◽  
Vol 20 (7) ◽  
pp. 12623-12651 ◽  
Author(s):  
Vasu Nair ◽  
Maurice Okello
Keyword(s):  
Integrase Inhibitor ◽  
Diketo Acids ◽  
Anti Hiv

scholarly journals Structural-Functional Analysis of 2,1,3-Benzoxadiazoles and Their N-oxides As HIV-1 Integrase Inhibitors

Acta Naturae ◽  
2013 ◽  
Vol 5 (1) ◽  
pp. 63-72 ◽  
Author(s):  
S. P. Korolev ◽  
O. V. Kondrashina ◽  
D. S. Druzhilovsky ◽  
A. M. Starosotnikov ◽  
M. D. Dutov ◽  
...  
Keyword(s):  
Integrase Inhibitor ◽  
Integrase Inhibitors ◽  
Mechanism Of Inhibition ◽  
Immunodeficiency Virus ◽  
Pharmacokinetic Properties ◽  
Nitro Derivatives ◽  
Derivatives Of ◽  
Anti Hiv ◽  
Hiv 1

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.

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 A novel anti-HIV active integrase inhibitor with a favorable in vitro cytochrome P450 and uridine 5′-diphospho-glucuronosyltransferase metabolism profile

2013 ◽  
Vol 98 (3) ◽  
pp. 365-372 ◽  
Author(s):  
Maurice O. Okello ◽  
Sanjay Mishra ◽  
Malik Nishonov ◽  
Marie K. Mankowski ◽  
Julie D. Russell ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Integrase Inhibitor ◽  
Anti Hiv

scholarly journals A unique conformational escape reaction of HIV-1 against an allosteric integrase inhibitor

2019 ◽  
Author(s):  
Tomofumi Nakamura ◽  
Teruya Nakamura ◽  
Masayuki Amano ◽  
Toshikazu Miyakawa ◽  
Yuriko Yamagata ◽  
...  
Keyword(s):  
Rna Binding ◽  
Integrase Inhibitor ◽  
Catalytic Core ◽  
Viral Particles ◽  
Dimerization Interface ◽  
Conformational Alteration ◽  
Escape Reaction ◽  
Viral Maturation ◽  
Anti Hiv ◽  
Hiv 1

AbstractHIV-1 integrase (IN) contributes to HIV-1 RNA binding, which is required for viral maturation. Non-catalytic site integrase inhibitors (NCINIs) have been developed as allosteric IN inhibitors, which perform anti-HIV-1 activity by disrupting IN multimerization. Here, we show that IN undergoes a novel conformational alteration to escape from NCINIs. We observed that NCINI-resistant HIV-1 variants have accumulated amino acid (AA) mutations in the IN-encoding region. We employed HPLC and thermal stability assays to show that the AA mutations affect the folding and dimerization interface of the IN catalytic core domains, resulting in severely decreased multimerization of full-length IN proteins (IN under-multimerization). The under-multimerization of IN was finally restored by HIV-1 RNA in the viral particles. Our study demonstrates that HIV-1 countervails NCINIs by IN under-multimerization as a novel escape mechanism. Our findings provide information on the understanding of IN multimerization and influence the development of unique anti-HIV-1 strategies.

scholarly journals A small molecule, ACAi-028, with anti-HIV-1 activity targets a novel hydrophobic pocket on HIV-1 capsid

2021 ◽  
Author(s):  
Tomofumi Nakamura ◽  
Travis chia ◽  
Masayuki Amano ◽  
Nobutoki Takamune ◽  
Masao Matsuoka ◽  
...  
Keyword(s):  
Thermal Stability ◽  
Reverse Transcriptase ◽  
Small Molecule ◽  
Early Stage ◽  
Integrase Inhibitor ◽  
Ionization Mass ◽  
Hydrophobic Pocket ◽  
Binding Model ◽  
Anti Hiv ◽  
Hiv 1

The human immunodeficiency virus type 1 (HIV-1) capsid (CA) is an essential viral component of HIV-1 infection, and an attractive therapeutic target for antivirals. We report that a small molecule, ACAi-028, inhibits HIV-1 replication by targeting a hydrophobic pocket in the N-terminal domain of CA (CA-NTD). ACAi-028 is one of more than 40 candidate anti-HIV-1 compounds identified by in silico screening and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Our binding model showed that ACAi-028 interacts with the Q13, S16, and T19 amino acid residues, via hydrogen bonds, in the targeting pocket of CA-NTD. Using recombinant fusion methods, TZM-bl, time-of-addition, and colorimetric reverse transcriptase (RT) assays, the compound was found to exert anti-HIV-1 activity in the early stage between a reverse transcriptase inhibitor, azidothymidine (AZT), and an integrase inhibitor, raltegravir (RAL), without any effect on RT activity, suggesting that this compound may affect HIV-1 core disassembly (uncoating). Moreover, electrospray ionization mass spectrometry (ESI-MS) also showed that the compound binds directly and non-covalently to the CA monomer. CA multimerization and thermal stability assays showed that ACAi-028 decreased CA multimerization and thermal stability via S16 or T19 residues.

scholarly journals Pharmacokinetics and dose-range finding toxicity of a novel anti-HIV active integrase inhibitor

2014 ◽  
Vol 108 ◽  
pp. 25-29 ◽  
Author(s):  
Vasu Nair ◽  
Maurice Okello ◽  
Sanjay Mishra ◽  
Jon Mirsalis ◽  
Kathleen O’Loughlin ◽  
...  
Keyword(s):  
Dose Range ◽  
Integrase Inhibitor ◽  
Range Finding ◽  
Anti Hiv
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