Identification of 5-Substituted 2-Acylaminothiazoles That Activate Tat-Mediated Transcription in HIV-1 Latency Models

Nguyen, William; Jacobson, Jonathan; Jarman, Kate E.; Sabroux, Hélène Jousset; Harty, Leigh; McMahon, James; Lewin, Sharon R.; Purcell, Damian F. J.; Sleebs, Brad E.

doi:10.1021/acs.jmedchem.9b00462

Cited by 12 publications

(6 citation statements)

References 44 publications

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“…5-CF 3 -1,3,4-oxadiazole scaffolds have emerged as valuable synthetic targets because of their appearance in numerous pharmaceuticals and bioactive molecules (Figure c) . Despite the fact that several powerful approaches to access these units have been achieved (Figure d), such as the dehydrative cycloaddition of 1,2-diacylhydrazines, the oxidative cycloaddition of N -acylhydrazones, the ring-opening/cycloaddition cascade of 5-trifluoromethyltetrazole or the corresponding sodium salt, the direct C–H oxidative trifluoromethylation of 2-aryl-1,3,4-oxadiazoles with TMSCF 3 , and the trifluoromethylation of activated 2-bromo-5-phenyl-1,3,4-oxadiazole with complex [Ph 4 P] + [Cu(CF 3 ) 2 ] − , the development of a novel strategy for the construction of 5-CF 3 -1,3,4-oxadiazoles under mild conditions still remains highly desirable.…”

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confidence: 99%

Diazotrifluoroethyl Radical: A CF₃-Containing Building Block in [3 + 2] Cycloaddition

et al. 2021

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We present herein a visible-light-induced [3 + 2] cycloaddition of a hypervalent iodine(III) reagent with α-ketoacids for the construction of 5-CF3-1,3,4-oxadiazoles that are of importance in medicinal chemistry. The reaction proceeds smoothly without a photocatalyst, metal, or additive under mild conditions. Different from the well-established trifluorodiazoethane (CF3CHN2), the diazotrifluoroethyl radical [CF3C(·)N2], a trifluoroethylcarbyne (CF3CĊ:) equivalent and an unusual CF3-containing building block, is involved in the present reaction system.

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confidence: 99%

Diazotrifluoroethyl Radical: A CF₃-Containing Building Block in [3 + 2] Cycloaddition

et al. 2021

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“…Furthermore, synergy could be observed between 103c and BETI JQ1 in various latent HIV-1 cellular models, indicating the prospects as effective LRAs for treating HIV-positive individuals. However, the exact cellular target(s) of these derivatives were still unclear [124]. models, indicating the prospects as effective LRAs for treating HIV-positive individuals.…”

Section: Av6 and Analoguesmentioning

confidence: 99%

“…Molecules 2023, 28, 3 29 of 40 models, indicating the prospects as effective LRAs for treating HIV-positive individuals. However, the exact cellular target(s) of these derivatives were still unclear [124].…”

Section: Dihydropyranoindole Derivativementioning

confidence: 99%

Medicinal Chemistry of Anti-HIV-1 Latency Chemotherapeutics: Biotargets, Binding Modes and Structure-Activity Relationship Investigation

Wang

Wei

et al. 2022

Molecules

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The existence of latent viral reservoirs (LVRs), also called latent cells, has long been an acknowledged stubborn hurdle for effective treatment of HIV-1/AIDS. This stable and heterogeneous reservoir, which mainly exists in resting memory CD4+ T cells, is not only resistant to highly active antiretroviral therapy (HAART) but cannot be detected by the immune system, leading to rapid drug resistance and viral rebound once antiviral treatment is interrupted. Accordingly, various functional cure strategies have been proposed to combat this barrier, among which one of the widely accepted and utilized protocols is the so-called ‘shock-and-kill’ regimen. The protocol begins with latency-reversing agents (LRAs), either alone or in combination, to reactivate the latent HIV-1 proviruses, then eliminates them by viral cytopathic mechanisms (e.g., currently available antiviral drugs) or by the immune killing function of the immune system (e.g., NK and CD8+ T cells). In this review, we focuse on the currently explored small molecular LRAs, with emphasis on their mechanism-directed drug targets, binding modes and structure-relationship activity (SAR) profiles, aiming to provide safer and more effective remedies for treating HIV-1 infection.

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“…We previously characterized a highly conserved element underlying the Tat open reading frame, named TIM-TAM (for Tat IRES modulator of tat mRNA) and characterized its role in controlling Tat translation through cap-and IRES-dependent mechanisms (Khoury et al, 2020). Moreover, we developed a model system to assess Tat cap and IRES translation (Nguyen et al, 2019).…”

Section: Knockdown Of Srp14 and Hmgb3 Impacts Tat Expression And Functionmentioning

confidence: 99%

The RNA-Binding Proteins SRP14 and HMGB3 Control HIV-1 Tat mRNA Processing and Translation During HIV-1 Latency

et al. 2021

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HIV-1 Tat protein is essential for virus production. RNA-binding proteins that facilitate Tat production may be absent or downregulated in resting CD4+ T-cells, the main reservoir of latent HIV in people with HIV (PWH) on antiretroviral therapy (ART). In this study, we examined the role of Tat RNA-binding proteins on the expression of Tat and control of latent and productive infection. Affinity purification coupled with mass spectrometry analysis was used to detect binding partners of MS2-tagged tat mRNA in a T cell-line model of HIV latency. The effect of knockdown and overexpression of the proteins of interest on Tat transactivation and translation was assessed by luciferase-based reporter assays and infections with a dual color HIV reporter virus. Out of the 243 interactions identified, knockdown of SRP14 (Signal Recognition Particle 14) negatively affected tat mRNA processing and translation as well as Tat-mediated transactivation, which led to an increase in latent infection. On the other hand, knockdown of HMGB3 (High Mobility Group Box 3) resulted in an increase in Tat transactivation and translation as well as an increase in productive infection. Footprinting experiments revealed that SRP14 and HMGB3 proteins bind to TIM-TAM, a conserved RNA sequence-structure in tat mRNA that functions as a Tat IRES modulator of tat mRNA. Overexpression of SRP14 in resting CD4+ T-cells from patients on ART was sufficient to reverse HIV-1 latency and induce virus production. The role of SRP14 and HMGB3 proteins in controlling HIV Tat expression during latency will be further assessed as potential drug targets.

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Identification of 5-Substituted 2-Acylaminothiazoles That Activate Tat-Mediated Transcription in HIV-1 Latency Models

Cited by 12 publications

References 44 publications

Diazotrifluoroethyl Radical: A CF₃-Containing Building Block in [3 + 2] Cycloaddition

Diazotrifluoroethyl Radical: A CF₃-Containing Building Block in [3 + 2] Cycloaddition

Medicinal Chemistry of Anti-HIV-1 Latency Chemotherapeutics: Biotargets, Binding Modes and Structure-Activity Relationship Investigation

The RNA-Binding Proteins SRP14 and HMGB3 Control HIV-1 Tat mRNA Processing and Translation During HIV-1 Latency

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Identification of 5-Substituted 2-Acylaminothiazoles That Activate Tat-Mediated Transcription in HIV-1 Latency Models

Cited by 12 publications

References 44 publications

Diazotrifluoroethyl Radical: A CF3-Containing Building Block in [3 + 2] Cycloaddition

Diazotrifluoroethyl Radical: A CF3-Containing Building Block in [3 + 2] Cycloaddition

Medicinal Chemistry of Anti-HIV-1 Latency Chemotherapeutics: Biotargets, Binding Modes and Structure-Activity Relationship Investigation

The RNA-Binding Proteins SRP14 and HMGB3 Control HIV-1 Tat mRNA Processing and Translation During HIV-1 Latency

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Diazotrifluoroethyl Radical: A CF₃-Containing Building Block in [3 + 2] Cycloaddition

Diazotrifluoroethyl Radical: A CF₃-Containing Building Block in [3 + 2] Cycloaddition