scholarly journals Design, Synthesis, Biochemical, and Antiviral Evaluations of C6 Benzyl and C6 Biarylmethyl Substituted 2-Hydroxylisoquinoline-1,3-diones: Dual Inhibition against HIV Reverse Transcriptase-Associated RNase H and Polymerase with Antiviral Activities

2014 ◽  
Vol 58 (2) ◽  
pp. 651-664 ◽  
Author(s):  
Sanjeev Kumar V. Vernekar ◽  
Zheng Liu ◽  
Eva Nagy ◽  
Lena Miller ◽  
Karen A. Kirby ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Rnase H ◽  
Hiv Reverse Transcriptase ◽  
Design Synthesis ◽  
Antiviral Activities ◽  
Dual Inhibition

scholarly journals Design, Synthesis, and Biological Evaluations of Hydroxypyridonecarboxylic Acids as Inhibitors of HIV Reverse Transcriptase Associated RNase H

2016 ◽  
Vol 59 (10) ◽  
pp. 5051-5062 ◽  
Author(s):  
Jayakanth Kankanala ◽  
Karen A. Kirby ◽  
Feng Liu ◽  
Lena Miller ◽  
Eva Nagy ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Rnase H ◽  
Hiv Reverse Transcriptase ◽  
Design Synthesis

scholarly journals Design, synthesis and biological evaluations of N-Hydroxy thienopyrimidine-2,4-diones as inhibitors of HIV reverse transcriptase-associated RNase H

2017 ◽  
Vol 141 ◽  
pp. 149-161 ◽  
Author(s):  
Jayakanth Kankanala ◽  
Karen A. Kirby ◽  
Andrew D. Huber ◽  
Mary C. Casey ◽  
Daniel J. Wilson ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Rnase H ◽  
Hiv Reverse Transcriptase ◽  
Design Synthesis

scholarly journals Effects of the W153L Substitution in HIV Reverse Transcriptase on Viral Replication and Drug Resistance to Multiple Categories of Reverse Transcriptase Inhibitors

2014 ◽  
Vol 58 (8) ◽  
pp. 4515-4526 ◽  
Author(s):  
Hong-Tao Xu ◽  
Susan P. Colby-Germinario ◽  
Maureen Oliveira ◽  
Daniel Rajotte ◽  
Richard Bethell ◽  
...  
Keyword(s):  
Viral Replication ◽  
Reverse Transcriptase ◽  
Rnase H ◽  
Hiv Reverse Transcriptase ◽  
Compound A ◽  
Enzymatic Function ◽  
Biochemical Assays ◽  
Rt Inhibitors ◽  
The Impact ◽  
Hiv 1

ABSTRACTA W153L substitution in HIV-1 reverse transcriptase (RT) was recently identified by selection with a novel nucleotide-competing RT inhibitor (NcRTI) termed compound A that is a member of the benzo[4,5]furo[3,2,d]pyrimidin-2-one NcRTI family of drugs. To investigate the impact of W153L, alone or in combination with the clinically relevant RT resistance substitutions K65R (change of Lys to Arg at position 65), M184I, K101E, K103N, E138K, and Y181C, on HIV-1 phenotypic susceptibility, viral replication, and RT enzymatic function, we generated recombinant RT enzymes and viruses containing each of these substitutions or various combinations of them. We found that W153L-containing viruses were impaired in viral replicative capacity and were hypersusceptible to tenofovir (TFV) while retaining susceptibility to most nonnucleoside RT inhibitors. The nucleoside 3TC retained potency against W153L-containing viruses but not when the M184I substitution was also present. W153L was also able to reverse the effects of the K65R substitution on resistance to TFV, and K65R conferred hypersusceptibility to compound A. Biochemical assays demonstrated that W153L alone or in combination with K65R, M184I, K101E, K103N, E138K, and Y181C impaired enzyme processivity and polymerization efficiency but did not diminish RNase H activity, providing mechanistic insights into the low replicative fitness associated with these substitutions. We show that the mechanism of the TFV hypersusceptibility conferred by W153L is mainly due to increased efficiency of TFV-diphosphate incorporation. These results demonstrate that compound A and/or derivatives thereof have the potential to be important antiretroviral agents that may be combined with tenofovir to achieve synergistic results.

1′,5′-Anhydrohexitol Oligonucleotides: Hybridisation and Strand Displacement with Oligoribonucleotides, Interaction with RNase H and HIV Reverse Transcriptase

1997 ◽  
Vol 3 (9) ◽  
pp. 1513-1520 ◽  
Author(s):  
Chris Hendrix ◽  
Helmut Rosemeyer ◽  
Bart De Bouvere ◽  
Arthur Van Aerschot ◽  
Frank Seela ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Rnase H ◽  
Strand Displacement ◽  
Hiv Reverse Transcriptase

Search for new therapeutics against HIV-1 via dual inhibition of RNase H and integrase: current status and future challenges

2021 ◽  
Author(s):  
Harsha Kharkwal ◽  
Banoth K Kumar ◽  
Sankaranarayanan Murugesan ◽  
Gautam Singhvi ◽  
Preeti Avasthi ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Active Sites ◽  
Rnase H ◽  
Current Status ◽  
Future Perspective ◽  
Striking Similarity ◽  
Future Challenges ◽  
Dual Inhibition ◽  
Viral Maturation ◽  
Hiv 1

Reverse transcriptase and integrase are key enzymes that play a pivotal role in HIV-1 viral maturation and replication. Reverse transcriptase consists of two active sites: RNA-dependent DNA polymerase and RNase H. The catalytic domains of integrase and RNase H share striking similarity, comprising two aspartates and one glutamate residue, also known as the catalytic DDE triad, and a Mg2+ pair. The simultaneous inhibition of reverse transcriptase and integrase can be a rational drug discovery approach for combating the emerging drug resistance problem. In the present review, the dual inhibition of RNase H and integrase is systematically discussed, including rationality of design, journey of development, advancement and future perspective.

Functional characterization of RNA-dependent DNA polymerase and RNase H activities of a recombinant HIV reverse transcriptase

Biochemistry ◽  
1991 ◽  
Vol 30 (10) ◽  
pp. 2651-2655 ◽  
Author(s):  
Cheng Keat Tan ◽  
Jian Zhang ◽  
Zhao Yan Li ◽  
W. Gary Tarpley ◽  
Kathleen M. Downey ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Dna Polymerase ◽  
Functional Characterization ◽  
Rnase H ◽  
Hiv Reverse Transcriptase

scholarly journals Design, Synthesis, and Antiviral Evaluation of Chimeric Inhibitors of HIV Reverse Transcriptase

2013 ◽  
Vol 4 (12) ◽  
pp. 1183-1188 ◽  
Author(s):  
Pinar Iyidogan ◽  
Todd J. Sullivan ◽  
Mahendra D. Chordia ◽  
Kathleen M. Frey ◽  
Karen S. Anderson
Keyword(s):  
Reverse Transcriptase ◽  
Hiv Reverse Transcriptase ◽  
Design Synthesis
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