2-Hydroxyisoquinoline-1,3(2<i>H</i>,4<i>H</i>)-diones (HIDs), Novel Inhibitors of HIV Integrase with a High Barrier to Resistance

Desimmie, Belete Ayele; Demeulemeester, Jonas; Suchaud, Virginie; Taltynov, Oliver; Billamboz, Muriel; Lion, Cédric; Bailly, Fabrice; Strelkov, S.V.; Debyser, Zeger; Cotelle, Philippe; Christ, Frauke

doi:10.1021/cb4000426

Cited by 23 publications

(23 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, compound 33 showed a profile similar to that of raltegravir and elvitegravir in time of addition experiments. 24 This attests for the cellular inhibition of integrase by this scaffold, whereas inhibition of the RT associated RNase H function remained a side activity. Half of the series showed an advantageous window between antiviral efficacy and cellular toxicity (21-to 86-fold).…”

mentioning

confidence: 92%

4-Substituted 2-Hydroxyisoquinoline-1,3(2H,4H)-diones as a Novel Class of HIV-1 Integrase Inhibitors

Billamboz

Suchaud

Bailly

et al. 2013

ACS Med. Chem. Lett.

Self Cite

View full text Add to dashboard Cite

A series of 2-hydroxy-1,3-dioxoisoquinoline-4-carboxamides featuring an N-hydroxyimide chelating functionality was evaluated for their inhibitory properties against human immunodeficiency virus type 1 integrase (HIV-1 IN). Several derivatives displayed low nanomolar IC 50 values comparable to that of the clinically used raltegravir. A marked effect of one compound on both primary IN-catalyzed reactions, strand transfer (ST), and 3′ processing (3′-P), emphasizes a novel IN inhibition mechanism establishing it as a potential new generation IN inhibitor. Substitution of the 2-hydroxyisoquinoline-1,3-dione scaffold at position 4 by carboxamido chains was beneficial for antiviral activity since reproducible low micromolar anti-HIV activities were obtained for the first time within this scaffold.

show abstract

mentioning

confidence: 92%

4-Substituted 2-Hydroxyisoquinoline-1,3(2H,4H)-diones as a Novel Class of HIV-1 Integrase Inhibitors

Billamboz

Suchaud

Bailly

et al. 2013

ACS Med. Chem. Lett.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Relative to RAL, EVG also shows a higher selectivity for the ST reaction over 3′-P (12,17). Several groups have developed new molecules with improved resistance profiles and some of the best compounds are effective 3′-P inhibitors (18–21). Based on this observation, we asked whether the 3′-P/ST selectivity of a drug could be linked to its ability to retain potency against the clinically important SH mutant.…”

Section: Introductionmentioning

confidence: 99%

Selectivity for strand-transfer over 3′-processing and susceptibility to clinical resistance of HIV-1 integrase inhibitors are driven by key enzyme–DNA interactions in the active site

et al. 2016

View full text Add to dashboard Cite

Integrase strand transfer inhibitors (INSTIs) are highly effective against HIV infections. Co-crystal structures of the prototype foamy virus intasome have shown that all three FDA-approved drugs, raltegravir (RAL), elvitegravir and dolutegravir (DTG), act as interfacial inhibitors during the strand transfer (ST) integration step. However, these structures give only a partial sense for the limited inhibition of the 3′-processing reaction by INSTIs and how INSTIs can be modified to overcome drug resistance, notably against the G140S-Q148H double mutation. Based on biochemical experiments with modified oligonucleotides, we demonstrate that both the viral DNA +1 and −1 bases, which flank the 3′-processing site, play a critical role for 3′-processing efficiency and inhibition by RAL and DTG. In addition, the G140S-Q148H (SH) mutant integrase, which has a reduced 3′-processing activity, becomes more active and more resistant to inhibition of 3′-processing by RAL and DTG in the absence of the −1 and +1 bases. Molecular modeling of HIV-1 integrase, together with biochemical data, indicate that the conserved residue Q146 in the flexible loop of HIV-1 integrase is critical for productive viral DNA binding through specific contacts with the virus DNA ends in the 3′-processing and ST reactions. The potency of integrase inhibitors against 3′-processing and their ability to overcome resistance is discussed.

show abstract

“…1) and β-thujaplicinol (compound #46) can suppress viral replication in cells by inhibiting the viral RNaseH (Hu et al, 2013; Tavis et al, 2013a). Here, we analyzed 2-hydroxyisoquinoline-1,3(2 H ,4 H )-dione (HID) derivatives (Billamboz et al, 2008; Billamboz et al, 2011a; Billamboz et al, 2011b; Billamboz et al, 2013; Desimmie et al, 2013; Hang et al, 2004; Klumpp et al, 2003; Suchaud et al, 2014) and structurally related compounds for their ability to inhibit HBV RNaseH activity and viral replication based on the ability of this compound class to inhibit the HIV enzyme, with the goal of determining whether HID compounds may be suitable for development as anti-HBV drugs.…”

Section: Introductionmentioning

confidence: 99%

Hepatitis B virus replication is blocked by a 2-hydroxyisoquinoline-1,3(2H,4H)-dione (HID) inhibitor of the viral ribonuclease H activity

et al. 2014

Self Cite

View full text Add to dashboard Cite

Nucleos(t)ide analog drugs profoundly suppress Hepatitis B Virus (HBV) replication but rarely cure the infection, so therapy is usually life-long. The nucleos(t)ide analogs inhibit the viral DNA polymerase and often push HBV to the brink of extinction, so it may be possible to eradicate HBV by suppressing HBV replication further. The HBV ribonuclease H (RNaseH) is a logical new drug target because it is the second of only two viral enzymes essential for viral replication. We recently developed a low throughput screening pipeline for inhibitors of the HBV RNaseH and viral replication. Here, we screened a series of twenty-three nitrogen-based polyoxygenated heterocycles including sixteen 2-hydroxyisoquinoline-1,3(2H,4H)-dione derivatives for anti-HBV RNaseH activity. Nine compounds inhibited the HBV RNaseH, but activity was marginal for eight of them. Compound #1 [2-hydroxyisoquinoline-1,3(2H,4H)-dione, HID] was the best hit with an IC50 of 28.1 µM and an EC50 of 4.2 µM. It preferentially suppressed accumulation of the viral plus-polarity DNA strand in replication inhibition assays, indicating that replication was blocked due to suppression of HBV RNaseH activity. It had a CC50 of 75 µM, yielding a therapeutic index of ~18. The EC50 value was 7-fold lower than the IC50, possibly due to cellular retention or metabolism of the compound, or higher affinity for the full-length enzyme than the recombinant form used for screening. These data indicate that the 2-hydroxyisoquinoline-1,3(2H,4H)-diones will have different structure-activity relationships for the HBV and HIV RNaseHs. Therefore, HID compounds may provide a foundation for development of more effective RNaseH inhibitors of HBV replication.

show abstract

2-Hydroxyisoquinoline-1,3(2H,4H)-diones (HIDs), Novel Inhibitors of HIV Integrase with a High Barrier to Resistance

Cited by 23 publications

References 39 publications

4-Substituted 2-Hydroxyisoquinoline-1,3(2H,4H)-diones as a Novel Class of HIV-1 Integrase Inhibitors

4-Substituted 2-Hydroxyisoquinoline-1,3(2H,4H)-diones as a Novel Class of HIV-1 Integrase Inhibitors

Selectivity for strand-transfer over 3′-processing and susceptibility to clinical resistance of HIV-1 integrase inhibitors are driven by key enzyme–DNA interactions in the active site

Hepatitis B virus replication is blocked by a 2-hydroxyisoquinoline-1,3(2H,4H)-dione (HID) inhibitor of the viral ribonuclease H activity

Contact Info

Product

Resources

About