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• W4200380633 endingPage "114901" @default.
• W4200380633 startingPage "114901" @default.
• W4200380633 abstract "The persistence of HIV-1 latent reservoir creates the major obstacle toward an HIV-1 cure. The shock and kill strategy aims to reverse HIV-1 proviral latency using latency-reversing agents (LRAs), thus boosting immune recognition and clearance to residual infected cells. Unfortunately, to date, none of these tested LRA candidates has been demonstrated effectiveness and/or safety in reactivation HIV-1 latency. The discovery and development of effective, safe and affordable LRA candidates are urgently needed for creating an HIV-1 functional cure. Here, we designed and synthesized a series of small-molecule phenoxyacetic acid derivatives based on the resveratrol scaffold and found one of them, named 5, 7-dimethoxy-2-(5-(methoxymethyl) furan-2-yl) quinazolin-4(3H)-one (Q205), effectively reactivated latent HIV-1 in latent HIV-1-infected cells without a corresponding increase in induction of potentially damaging cytokines. The molecular mechanism of Q205 is shown to increase the phosphorylation of the CDK9 T-loop at position Thr186, dissociate positive transcription elongation factor b (P-TEFb) from BRD4, and promote the Tat-mediated HIV-1 transcription and RNA polymerase II (RNAPII) C-terminal domain (CTD) on Ser (CTD-Ser2P) to bind to the HIV-1 promoter. This study provides a unique insight into resveratrol modified derivatives as promising leads for preclinical LRAs, which in turn may help toward inhibitor design and chemical optimization for improving HIV-1 shock-and kill-based efforts." @default.
• W4200380633 created "2021-12-31" @default.
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• W4200380633 date "2022-03-01" @default.
• W4200380633 modified "2023-10-10" @default.
• W4200380633 title "A synthetic resveratrol analog termed Q205 reactivates latent HIV-1 through activation of P-TEFb" @default.
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• W4200380633 doi "https://doi.org/10.1016/j.bcp.2021.114901" @default.
• W4200380633 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/34971588" @default.
• W4200380633 hasPublicationYear "2022" @default.
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