Transient kinetic analyses of the ribonuclease H cleavage activity of HIV-1 reverse transcriptase in complex with efavirenz and/or a β-thujaplicinol analogue

2013 ◽  
Vol 455 (2) ◽  
pp. 179-184 ◽  
Author(s):  
Brian D. Herman ◽  
Nicolas Sluis-Cremer
Keyword(s):  
Steady State ◽  
Reverse Transcriptase ◽  
Rnase H ◽  
Ribonuclease H ◽  
Cleavage Activity ◽  
Steady State Kinetics ◽  
Hiv 1

Pre-steady-state kinetics were used to define the mechanisms by which efavirenz and a β-thujaplicinol analogue modulate the RNase H activity of HIV-1 reverse transcriptase. Both inhibitors do not affect polymerase-dependent cleavages, but significantly affect the rates of polymerase-independent cleavages.

Prediction of the binding mode and resistance profile for a dual-target pyrrolyl diketo acid scaffold against HIV-1 integrase and reverse-transcriptase-associated ribonuclease H

2018 ◽  
Vol 20 (37) ◽  
pp. 23873-23884 ◽  
Author(s):  
Fengyuan Yang ◽  
Guoxun Zheng ◽  
Tingting Fu ◽  
Xiaofeng Li ◽  
Gao Tu ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Binding Mode ◽  
Hiv Treatment ◽  
Rnase H ◽  
Ribonuclease H ◽  
Resistance Profile ◽  
Anti Hiv ◽  
Hiv 1 ◽  
Dual Target

The recently developed pyrrolyl diketo acid scaffold targeting both HIV-1 IN and RNase H is beneficial to counteract the failure of anti-HIV treatment due to drug resistance.

Small-molecule Inhibitors of HIV-1 Reverse Transcriptase-Associated Ribonuclease H function: Challenges and Recent Developments.

2021 ◽  
Vol 28 ◽  
Author(s):  
Valentina Noemi Madia ◽  
Antonella Messorea ◽  
Alessandro De Leo ◽  
Valeria Tudino ◽  
Ivano Pindinello ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Small Molecules ◽  
High Specificity ◽  
Antiretroviral Drugs ◽  
Rnase H ◽  
Ribonuclease H ◽  
Clinical Phase ◽  
Recent Developments ◽  
Open Issue ◽  
Hiv 1

: Multiple combination of antiretroviral drugs has remarkably improved the treatment of HIV-1 infection. However, life-long treatments and drug resistance are a still open issue that requires continuous efforts for identification of novel antiviral drugs. Background: the reverse transcriptase-associated ribonuclease H (RNase H) hydrolyzes the HIV genome to allow synthesizing viral DNA. Currently, no RNase H inhibitors (RHIs) have reached the clinical phase. Therefore, RNase H can be defined as an attractive target for drug design. Objective: despite the wealth of information available for RNase H domain, the development of RHIs with high specificity and low cellular toxicity has been disappointing. However, it is now becoming increasingly evident that reverse transcriptase is a highly versatile enzyme, undergoing major structural alterations to complete its catalysis, and that exists a close spatial and temporal interplay between reverse transcriptase polymerase and RNase H domains. This review sums up the present dares in targeting RNase H encompassing the challenges in selectively inhibiting RNase H vs polymerase and/or HIV-1 integrase and the weak antiviral activity of active site inhibitors, probably for a substrate barrier that impedes small molecules to reach the targeted site. Moreover, focus is given on the most recent progresses in the field of medicinal chemistry that have led to the identification of several small molecules as RHIs in the last few years. Conclusion: RHIs could be a new class of drugs with novel mechanism of action highly precious for the treatment of resistant HIV strains.

scholarly journals Steady state kinetics and inhibition of HIV-1 reverse transcriptase by a non-nucleoside dipyridodiazepinone, BI-RG-587, using a heteropolymeric template

1991 ◽  
Vol 19 (11) ◽  
pp. 3035-3039 ◽  
Author(s):  
Elizabeth B. Kopp ◽  
John J. Miglietta ◽  
Anthony G. Shrutkowski ◽  
Cheng-Kon Shih ◽  
Peter M. Grob ◽  
...  
Keyword(s):  
Steady State ◽  
Reverse Transcriptase ◽  
Steady State Kinetics ◽  
Hiv 1

scholarly journals 1,2,4-Triazolo[1,5-a]pyrimidines as a Novel Class of Inhibitors of the HIV-1 Reverse Transcriptase-Associated Ribonuclease H Activity

Molecules ◽  
2020 ◽  
Vol 25 (5) ◽  
pp. 1183 ◽  
Author(s):  
Jenny Desantis ◽  
Serena Massari ◽  
Angela Corona ◽  
Andrea Astolfi ◽  
Stefano Sabatini ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Rnase H ◽  
Ribonuclease H ◽  
Allosteric Site ◽  
Viral Reservoirs ◽  
Enzymatic Function ◽  
Immunodeficiency Virus ◽  
Resistant Strains ◽  
Drug Resistant Strains ◽  
Hiv 1

Despite great efforts have been made in the prevention and therapy of human immunodeficiency virus (HIV-1) infection, however the difficulty to eradicate latent viral reservoirs together with the emergence of multi-drug-resistant strains require the search for innovative agents, possibly exploiting novel mechanisms of action. In this context, the HIV-1 reverse transcriptase (RT)-associated ribonuclease H (RNase H), which is one of the few HIV-1 encoded enzymatic function still not targeted by any current drug, can be considered as an appealing target. In this work, we repurposed in-house anti-influenza derivatives based on the 1,2,4-triazolo[1,5-a]-pyrimidine (TZP) scaffold for their ability to inhibit HIV-1 RNase H function. Based on the results, a successive multi-step structural exploration around the TZP core was performed leading to identify catechol derivatives that inhibited RNase H in the low micromolar range without showing RT-associated polymerase inhibitory activity. The antiviral evaluation of the compounds in the MT4 cells showed any activity against HIV-1 (IIIB strain). Molecular modelling and mutagenesis analysis suggested key interactions with an unexplored allosteric site providing insights for the future optimization of this class of RNase H inhibitors.

scholarly journals Garcinol from Garcinia indica inhibits HIV‐1 reverse transcriptase‐associated ribonuclease H

2021 ◽  
Author(s):  
Angela Corona ◽  
Sebastian Seibt ◽  
David Schaller ◽  
Rainer Schobert ◽  
Andrea Volkamer ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Ribonuclease H ◽  
Garcinia Indica ◽  
Hiv 1
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