Structure–Activity Relationship of Pyrrolyl Diketo Acid Derivatives as Dual Inhibitors of HIV-1 Integrase and Reverse Transcriptase Ribonuclease H Domain

Crucitti, Giuliana Cuzzucoli; Métifiot, Mathieu; Pescatori, Luca; Messore, Antonella; Madia, Valentina Noemi; Pupo, Giovanni; Saccoliti, Francesco; Scipione, Luigi; Tortorella, Silvano; Esposito, Francesca; Corona, Angela; Cadeddu, Marta; Marchand, Christophe; Pommier, ﻿Yves; Tramontano, Enzo; Costi, Roberta; Santo, Roberto Di

doi:10.1021/jm501799k

Cited by 66 publications

(37 citation statements)

References 44 publications

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“…[5] Whereas no RNase Hinhibitor has reached clinicaltrials, alimited number of compounds have been reported, and they can be classifiedi nto two classes:m etal-chelating active-site inhibitors, which bind andc oordinate the two Mg 2 + ion cofactors, and allosteric inhibitors, which induce ac onformational change in the active site that disables the RNA:DNA hybrid substrate binding. [6][7][8][9][10] Allosteric inhibitors could be attractive both to counteract the development of resistants trains and to avoid the inhibition of relatedh ost enzymes, such as the humanR Nase H1. [11] Despite the significant progress achieved with combination antiretroviral therapy in the fight against human immunodeficiency virus (HIV) infection, the difficulty to eradicate the virus together with the rapid emergenceo fm ultidrug-resistant strains clearly underline ap ressing need for innovative agents, possibly endowed with novel mechanismso fa ction.…”

Section: Introductionmentioning

confidence: 99%

Studies on Cycloheptathiophene‐3‐carboxamide Derivatives as Allosteric HIV‐1 Ribonuclease H Inhibitors

et al. 2016

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Despite the significant progress achieved with combination antiretroviral therapy in the fight against human immunodeficiency virus (HIV) infection, the difficulty to eradicate the virus together with the rapid emergence of multidrug-resistant strains clearly underline a pressing need for innovative agents, possibly endowed with novel mechanisms of action. In this context, owing to its essential role in HIV genome replication, the reverse transcriptase associated ribonuclease H (RNase H) has proven to be an appealing target. To identify new RNase H inhibitors, an in-house cycloheptathiophene-3-carboxamide library was screened; this led to compounds endowed with inhibitory activity, the structural optimization of which led to the catechol derivative 2-(3,4-dihydroxybenzamido)-N-(pyridin-2-yl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide (compound 33) with an IC50 value on the RNase H activity in the nanomolar range. Mechanistic studies suggested selective inhibition of the RNase H through binding to an innovative allosteric site, which could be further exploited to enrich this class of inhibitors.

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Section: Introductionmentioning

confidence: 99%

Studies on Cycloheptathiophene‐3‐carboxamide Derivatives as Allosteric HIV‐1 Ribonuclease H Inhibitors

et al. 2016

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“…Pyrrolyl DKA derivatives were further explored to optimize dual inhibitors against IN and RNase H [ 141 ]. Two classes of pyrrolyl DKA derivatives were reported: the diketobutanoic and the diketohexenoic derivatives.…”

Section: Inis Approved For Clinical Applicationmentioning

confidence: 99%

Recent Advances in the Discovery of Small-Molecule Inhibitors of HIV-1 Integrase

Choi

Mallareddy

et al. 2018

Future Sci. OA

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AIDS caused by the infection of HIV is a prevalent problem today. Rapid development of drug resistance to existing drug classes has called for the discovery of new targets. Within the three major enzymes (i.e., HIV-1 protease, HIV-1 reverse transcriptase and HIV-1 integrase [IN]) of the viral replication cycle, HIV-1 IN has been of particular interest due to the absence of human cellular homolog. HIV-1 IN catalyzes the integration of viral genetic material with the host genome, a key step in the viral replication process. Several novel classes of HIV IN inhibitors have been explored by targeting different sites on the enzyme. This review strives to provide readers with updates on the recent developments of HIV-1 IN inhibitors.

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“…All these findings confirm our initial hypothesis of multiple target binding. Unlike the known molecules capable of dual IN/RNase H inhibition or dual RDDP/RNase H inhibition, kuwanon‐L represents the first compound able to inhibit both the activity associated with HIV‐1 IN and the two activities associated with HIV‐1 RT. This new approach can be considered a solid starting point that demonstrates that the multiple‐target‐binding strategy can be successfully applied against HIV‐1.…”

Section: Figurementioning

confidence: 99%

Natural Product Kuwanon‐L Inhibits HIV‐1 Replication through Multiple Target Binding

et al. 2017

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In recent years many advances have been made in the fight against HIV-1 infection. However, the lack of a vaccine, together with the increasing resistance to the highly active anti-retroviral therapy (HAART), make HIV-1 infection still a serious global emergency. Thus, new compounds with original modes of action are continuously required, and natural products have ever been a very interesting class of pharmacologically active molecules. Some of them have been used since ancient times against viral infections. Here we present a work in which we suggest that kuwanon-L, a natural product active as an HIV-1 integrase (IN) inhibitor, might exert its overall antiviral activity through binding to multiple viral targets. Specific enzymatic tests, together with a time-of-addition (TOA) experiment, support our hypothesis of binding both to IN and to reverse transcriptase (RT). Overall, this compound can be considered an attractive lead for the development of new classes of antiviral agents able to overcome the problem of resistance, due to its ability to exert its action by binding simultaneously to multiple viral targets.

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Structure–Activity Relationship of Pyrrolyl Diketo Acid Derivatives as Dual Inhibitors of HIV-1 Integrase and Reverse Transcriptase Ribonuclease H Domain

Cited by 66 publications

References 44 publications

Studies on Cycloheptathiophene‐3‐carboxamide Derivatives as Allosteric HIV‐1 Ribonuclease H Inhibitors

Studies on Cycloheptathiophene‐3‐carboxamide Derivatives as Allosteric HIV‐1 Ribonuclease H Inhibitors

Recent Advances in the Discovery of Small-Molecule Inhibitors of HIV-1 Integrase

Natural Product Kuwanon‐L Inhibits HIV‐1 Replication through Multiple Target Binding

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