Inhibitory Effect of 2,3,5,6-Tetrafluoro-4-[4-(aryl)-1H-1,2,3-triazol-1-yl]benzenesulfonamide Derivatives on HIV Reverse Transcriptase Associated RNase H Activities

Pala, Nicolino; Esposito, Francesca; Rogolino, Dominga; Carcelli, Mauro; Sanna, Vanna; Palomba, Michele Francesco Luigi; Naesens, Lieve; Corona, Angela; Grandi, Nicole; Sechi, Mario

doi:10.3390/ijms17081371

Cited by 13 publications

(6 citation statements)

References 46 publications

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“…They synthesized 48 derivatives, and the most potent compound contained a primary benzenesulfonamide group (4-PhSO 2 NH 2 ) that made H bonds with K104 and V106 in RT. An earlier study by Masuda et al also found benzenesulfonamide derivatives with inhibitory activity against HIV-1 with WT or NNRTI-resistant mutant RT (33), while Pala et al found benzenesulfonamide derivatives that inhibited HIV-1 RT RNase H (34). Together, these findings suggest that benzenesulfonamide-derived compounds may have more than one anti-HIV-1 activity and more than one anti-RT activity, and our data indicate that one of these activities inhibits RT interaction with cellular eEF1A.…”

Section: Discussionmentioning

confidence: 98%

Oxazole-Benzenesulfonamide Derivatives Inhibit HIV-1 Reverse Transcriptase Interaction with Cellular eEF1A and Reduce Viral Replication

Rawle

et al. 2019

J Virol

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HIV-1 replication requires direct interaction between HIV-1 reverse transcriptase (RT) and cellular eukaryotic translation elongation factor 1A (eEF1A). Our previous work showed that disrupting this interaction inhibited HIV-1 uncoating, reverse transcription, and replication, indicating its potential as an anti-HIV-1 target. In this study, we developed a sensitive, live-cell split-luciferase complementation assay (NanoBiT) to quantitatively measure inhibition of HIV-1 RT interaction with eEF1A. We used this to screen a small molecule library and discovered small-molecule oxazole-benzenesulfonamides (C7, C8, and C9), which dose dependently and specifically inhibited the HIV-1 RT interaction with eEF1A. These compounds directly bound to HIV-1 RT in a dose-dependent manner, as assessed by a biolayer interferometry (BLI) assay, but did not bind to eEF1A. These oxazole-benzenesulfonamides did not inhibit enzymatic activity of recombinant HIV-1 RT in a homopolymer assay but did inhibit reverse transcription and infection of both wild-type (WT) and nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistant HIV-1 in a dose-dependent manner in HEK293T cells. Infection of HeLa cells was significantly inhibited by the oxazole-benzenesulfonamides, and the antiviral activity was most potent against replication stages before 8 h postinfection. In human primary activated CD4+ T cells, C7 inhibited HIV-1 infectivity and replication up to 6 days postinfection. The data suggest a novel mechanism of HIV-1 inhibition and further elucidate how the RT-eEF1A interaction is important for HIV-1 replication. These compounds provide potential to develop a new class of anti-HIV-1 drugs to treat WT and NNRTI-resistant strains in people infected with HIV. IMPORTANCE Antiretroviral drugs protect many HIV-positive people, but their success can be compromised by drug-resistant strains. To combat these strains, the development of new classes of HIV-1 inhibitors is essential and a priority in the field. In this study, we identified small molecules that bind directly to HIV-1 reverse transcriptase (RT) and inhibit its interaction with cellular eEF1A, an interaction which we have previously identified as crucial for HIV-1 replication. These compounds inhibit intracellular HIV-1 reverse transcription and replication of WT HIV-1, as well as HIV-1 mutants that are resistant to current RT inhibitors. A novel mechanism of action involving inhibition of the HIV-1 RT-eEF1A interaction is an important finding and a potential new way to combat drug-resistant HIV-1 strains in infected people.

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Section: Discussionmentioning

confidence: 98%

Oxazole-Benzenesulfonamide Derivatives Inhibit HIV-1 Reverse Transcriptase Interaction with Cellular eEF1A and Reduce Viral Replication

Rawle

et al. 2019

J Virol

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“…Besides the abovementioned 1,2,3‐triazole hybrids, some other 1,2,3‐triazole hybrids also showed a certain anti‐HIV activity, but almost all of them were far less potent than the references. [ 88–96 ] For example, the 1,2,3‐triazole–quinoline hybrid 33 (IC 50 : 800 nM) exhibited promising activity against HIV‐1 RT, but the activity was far inferior to that of AZT (IC 50 : 10 nM). [ 88 ] Despite this, the SAR was enriched, and the enriched SAR may pave the way for further rational design.…”

Section: Miscellaneous 123‐triazole Hybridsmentioning

confidence: 99%

1,2,3‐Triazole hybrids with anti‐HIV‐1 activity

Feng

Zheng

Zhao

et al. 2020

Archiv der Pharmazie

103

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The human immunodeficiency virus type 1 (HIV‐1) is the major etiological agent responsible for the acquired immunodeficiency syndrome (AIDS), which is a serious infectious disease and remains one of the most prevalent problems at present. Currently, combined antiretroviral therapy is the primary modality for the treatment and management of HIV/AIDS, but the long‐term use can result in major drawbacks such as the development of multidrug‐resistant viruses and multiple side effects. 1,2,3‐Triazole is the common framework in the development of new drugs, and its derivatives have the potential to inhibit various HIV‐1 enzymes such as reverse transcriptase, integrase, and protease, consequently possessing a potential anti‐HIV‐1 activity. This review covers the recent advances regarding the 1,2,3‐triazole hybrids with potential anti‐HIV‐1 activity; it focuses on the chemical structures, structure–activity relationship, and mechanisms of action, covering articles published from 2010 to 2020.

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“…Derivatives of 4-(aryltriazolyl)-benzenesulfonamide emerged as novel scaffolds for RNase H inhibition as the result of focused screening campaigns using molecules specifically designed as metalloenzyme inhibitors (Pala et al, 2016). In this case, an interesting approach was used to adapt the electron density distribution of the inhibitor in order to have, at physiological conditions, a compound with higher affinity for the Mg 2+ cofactors within the RNase H active site.…”

Section: Benzenesulfonamidesmentioning

confidence: 99%

Ribonuclease H, an unexploited target for antiviral intervention against HIV and hepatitis B virus

2019

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Inhibitory Effect of 2,3,5,6-Tetrafluoro-4-[4-(aryl)-1H-1,2,3-triazol-1-yl]benzenesulfonamide Derivatives on HIV Reverse Transcriptase Associated RNase H Activities

Cited by 13 publications

References 46 publications

Oxazole-Benzenesulfonamide Derivatives Inhibit HIV-1 Reverse Transcriptase Interaction with Cellular eEF1A and Reduce Viral Replication

Oxazole-Benzenesulfonamide Derivatives Inhibit HIV-1 Reverse Transcriptase Interaction with Cellular eEF1A and Reduce Viral Replication

1,2,3‐Triazole hybrids with anti‐HIV‐1 activity

Ribonuclease H, an unexploited target for antiviral intervention against HIV and hepatitis B virus

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