“Old Dogs with New Tricks”: exploiting alternative mechanisms of action and new drug design strategies for clinically validated HIV targets

Kang, Dongwei; Song, Yuning; Chen, Wenmin; Zhan, Peng; Liu, Xinyong

doi:10.1039/c4mb00147h

Cited by 25 publications

(12 citation statements)

References 134 publications

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“…While HAART has proven to effectively suppress viral replication, the required long term HAART treatment can be plagued by adverse effects and drug resistance. This is precisely why even with a large number of FDA-approved drugs there is still a pressing need for improved antivirals, particularly those with novel and distinct mechanisms of action [3, 4] to combat drug resistance. Of all FDA-approved HIV drugs, inhibitors of RT comprise two distinct classes, nucleoside RT inhibitors (NRTIs) [5] and non-nucleoside RT inhibitors (NNRTIs) [6], and are of particular importance for HAART.…”

Section: Introductionmentioning

confidence: 99%

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

Kankanala

Kirby

Huber

et al. 2017

European Journal of Medicinal Chemistry

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Human immunodeficiency virus (HIV) reverse transcriptase (RT) associated ribonuclease H (RNase H) is the only HIV enzymatic function not targeted by current antiviral drugs. Although various chemotypes have been reported to inhibit HIV RNase H, few have shown significant antiviral activities. We report herein the design, synthesis and biological evaluation of a novel N-hydroxy thienopyrimidine-2,3-dione chemotype (11) which potently and selectively inhibited RNase H with considerable potency against HIV-1 in cell culture. Current structure-activity-relationship (SAR) identified analogue 11d as a nanomolar inhibitor of RNase H (IC50 = 0.04 μM) with decent antiviral potency (EC50 = 7.4 μM) and no cytotoxicity (CC50 > 100 μM). In extended biochemical assays compound 11d did not inhibit RT polymerase (pol) while inhibiting integrase strand transfer (INST) with 53 fold lower potency (IC50 = 2.1 μM) than RNase H inhibition. Crystallographic and molecular modeling studies confirmed the RNase H active site binding mode.

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Section: Introductionmentioning

confidence: 99%

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

Kankanala

Kirby

Huber

et al. 2017

European Journal of Medicinal Chemistry

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“…Based on these analysis and in connection with our previous endeavor to seek novel, potent, selective, and less toxic antiviral agents from fused heterocycles, we started to explore the privileged and synthetically feasible purine derivatives as more potent anti‐HIV agents via structure‐based bioisosteric replacement and molecular hybridization, in the hope that the new analogs may have somewhat better properties . Concretely, as shown in Figure S1, the bridgehead nitrogen‐containing bicyclic scaffolds were replaced by the purine ring, and the preferred N ‐(piperidin‐4‐yl)amine group was installed at the right‐wing portion of the purine core.…”

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confidence: 99%

Synthesis and Preliminary Antiviral Activities of Piperidine‐substituted Purines against HIV and Influenza A/H1N1 Infections

et al. 2015

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We have developed a series of N(2) -(1-(substituted-aryl)piperidin-4-yl)-N(6) -mesityl-9H-purine-2,6-diamine derivatives as potent antiviral agents. Preliminary biological evaluation indicated that nearly half of them possessed remarkable HIV inhibitory potencies in cellular assays. In particular, FZJ13 appeared to be the most notable one, which displayed anti-HIV-1 activity compared to 3TC. Moreover, an unexpected finding was that FZJ05 displayed significant potency against influenza A/H1N1 (strain A/PR/8/34) in Madin-Darby canine kidney cells with EC50 values much lower than those of ribavirin, amantadine, and rimantadine. The results suggest that these novel purine derivatives have the potential to be further developed as new therapeutic agents against HIV-1 or influenza virus.

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“…Despite inhibiting the RT function only at a micromolar range, the two compounds can serve as scaffold for further development, e.g., in fragment-based ligand design [36], given the need of alternative NNRTIs in the increasing emergence of viral drug cross resistance mutations [34]. Our limited mice experiments (unpublished) showed no obvious toxicity effects at dosages up to 7 mg/kg for both the compounds, preliminarily showing them to be relatively safe.…”

Section: Discussionmentioning

confidence: 78%

An Alternative HIV-1 Non-Nucleoside Reverse Transcriptase Inhibition Mechanism: Targeting the p51 Subunit

Chan

Krah

et al. 2020

Molecules

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The ongoing development of drug resistance in HIV continues to push for the need of alternative drug targets in inhibiting HIV. One such target is the Reverse transcriptase (RT) enzyme which is unique and critical in the viral life cycle—a rational target that is likely to have less off-target effects in humans. Serendipitously, we found two chemical scaffolds from the National Cancer Institute (NCI) Diversity Set V that inhibited HIV-1 RT catalytic activity. Computational structural analyses and subsequent experimental testing demonstrated that one of the two chemical scaffolds binds to a novel location in the HIV-1 RT p51 subunit, interacting with residue Y183, which has no known association with previously reported drug resistance. This finding supports the possibility of a novel druggable site on p51 for a new class of non-nucleoside RT inhibitors that may inhibit HIV-1 RT allosterically. Although inhibitory activity was shown experimentally to only be in the micromolar range, the scaffolds serve as a proof-of-concept of targeting the HIV RT p51 subunit, with the possibility of medical chemistry methods being applied to improve inhibitory activity towards more effective drugs.

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“Old Dogs with New Tricks”: exploiting alternative mechanisms of action and new drug design strategies for clinically validated HIV targets

Cited by 25 publications

References 134 publications

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

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

Synthesis and Preliminary Antiviral Activities of Piperidine‐substituted Purines against HIV and Influenza A/H1N1 Infections

An Alternative HIV-1 Non-Nucleoside Reverse Transcriptase Inhibition Mechanism: Targeting the p51 Subunit

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