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.

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.

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.

Design, synthesis, and biological evaluation of novel trifluoromethyl indoles as potent HIV-1 NNRTIs with an improved drug resistance profile

2014 ◽  
Vol 12 (21) ◽  
pp. 3446-3458 ◽  
Author(s):  
Hai-Xia Jiang ◽  
Dao-Min Zhuang ◽  
Ying Huang ◽  
Xing-Xin Cao ◽  
Jian-Hua Yao ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Biological Evaluation ◽  
Design Synthesis ◽  
Resistance Profile ◽  
Drug Resistance Profile ◽  
Synthesis And Biological Evaluation ◽  
Anti Hiv ◽  
Hiv 1

A novel series of trifluoromethyl indoles have been designed, synthesized and evaluated for anti-HIV-1 activities.

Recent Advances in Computer-aided Antiviral Drug Design Targeting HIV-1 Integrase and Reverse Transcriptase Associated Ribonuclease H

2021 ◽  
Vol 28 ◽  
Author(s):  
Fengyuan Yang ◽  
Jingyi Yang ◽  
Zhao Zhang ◽  
Gao Tu ◽  
Xiaojun Yao ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Drug Design ◽  
Reverse Transcriptase ◽  
Antiviral Drug ◽  
Antiviral Drugs ◽  
Rnase H ◽  
Energy Calculation ◽  
Recent Advances ◽  
Computer Aided ◽  
Hiv 1

: Acquired immunodeficiency syndrome (AIDS) has been a chronic, life-threatening disease for a long time. However, a broad range of antiretroviral drug regimens are applicable for the successful suppression of virus replication in human immunodeficiency virus type 1 (HIV-1) infected people. The mutation-induced drug resistance problems during the treatment of AIDS forced people to continuously look for new antiviral agents. HIV-1 integrase (IN) and reverse transcriptase associated ribonuclease (RT-RNase H), two pivotal enzymes in HIV-1 replication progress, has gain popularity as drug-able targets for designing novel HIV-1 antiviral drugs. During the development of HIV-1 IN and/or RT-RNase H inhibitors, computer-aided drug design (CADD), including homology modeling, pharmacophore, docking, molecular dynamics (MD) simulation, and binding free energy calculation, represents a significant tool to accelerate the discovery of new drug candidates and reduce costs in antiviral drug development. In this review, we summarized the recent advances in the design of single-and dual-target inhibitors against HIV-1 IN or/and RT-RNase H as well as the prediction of mutation-induced drug resistance based on computational methods. We highlighted the results of the reported literature and proposed some perspectives on the design of novel and more effective antiviral drugs in the future.

scholarly journals Structure-guided approach identifies a novel class of HIV-1 ribonuclease H inhibitors: binding mode insights through magnesium complexation and site-directed mutagenesis studies

MedChemComm ◽  
2018 ◽  
Vol 9 (3) ◽  
pp. 562-575 ◽  
Author(s):  
Vasanthanathan Poongavanam ◽  
Angela Corona ◽  
Casper Steinmann ◽  
Luigi Scipione ◽  
Nicole Grandi ◽  
...  
Keyword(s):  
In Silico ◽  
Binding Mode ◽  
Rnase H ◽  
Site Directed Mutagenesis ◽  
Ribonuclease H ◽  
Directed Mutagenesis ◽  
New Class ◽  
Hiv 1

In silico methods identified a new class of inhibitors for HIV-1 RT RNase H and magnesium complexation study reveals the binding mode of these compounds.

scholarly journals In Vitro Anti-HIV-1 Reverse Transcriptase and Integrase Properties of Punica granatum L. Leaves, Bark, and Peel Extracts and Their Main Compounds

Plants ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2124
Author(s):  
Cinzia Sanna ◽  
Arianna Marengo ◽  
Stefano Acquadro ◽  
Alessia Caredda ◽  
Roberta Lai ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Ellagic Acid ◽  
Punica Granatum ◽  
Rnase H ◽  
Hydrolyzable Tannins ◽  
Ic50 Values ◽  
Anti Hiv ◽  
Punica Granatum L ◽  
Hiv 1

In a search for natural compounds with anti-HIV-1 activity, we studied the effect of the ethanolic extract obtained from leaves, bark, and peels of Punica granatum L. for the inhibition of the HIV-1 reverse transcriptase (RT)-associated ribonuclease H (RNase H) and integrase (IN) LEDGF-dependent activities. The chemical analyses led to the detection of compounds belonging mainly to the phenolic and flavonoid chemical classes. Ellagic acid, flavones, and triterpenoid molecules were identified in leaves. The bark and peels were characterized by the presence of hydrolyzable tannins, such as punicalins and punicalagins, together with ellagic acid. Among the isolated compounds, the hydrolyzable tannins and ellagic acid showed a very high inhibition (IC50 values ranging from 0.12 to 1.4 µM and 0.065 to 0.09 µM of the RNase H and IN activities, respectively). Of the flavonoids, luteolin and apigenin were found to be able to inhibit RNase H and IN functions (IC50 values in the 3.7–22 μM range), whereas luteolin 7-O-glucoside showed selective activity for HIV-1 IN. In contrast, betulinic acid, ursolic acid, and oleanolic acid were selective for the HIV-1 RNase H activity. Our results strongly support the potential of non-edible P. granatum organs as a valuable source of anti-HIV-1 compounds.

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.

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