2. Academic Validation
  3. A synthetic resveratrol analog termed Q205 reactivates latent HIV-1 through activation of P-TEFb

A synthetic resveratrol analog termed Q205 reactivates latent HIV-1 through activation of P-TEFb

  • Biochem Pharmacol. 2022 Mar;197:114901. doi: 10.1016/j.bcp.2021.114901.
Taizhen Liang 1,  Ziyao Wu 1,  Yibin Li 1,  Chao Li 1,  Kangni Zhao 2,  Xinman Qiao 1,  Heng Duan 3,  Xuanxuan Zhang 4,  Shuwen Liu 1,  Baomin Xi 5,  Lin Li 6
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of New Drug Screening, Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, PR China.
  • 2 School of Public Health, Southern Medical University, Guangzhou 510515, PR China. Electronic address: zhaokangni@icloud.com.
  • 3 Department of Pharmacy, Stomatological Hospital, Southern Medical University, Guangzhou, Guangdong 510280, PR China.
  • 4 Center for Drug Research and Development, Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Key Laboratory of New Drug Discovery and Evaluation of Ordinary Universities of Guangdong Province, Guangdong Pharmaceutical University, Guangzhou, Guangdong 510006, PR China.
  • 5 Guangdong Provincial Key Laboratory of New Drug Screening, Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, PR China. Electronic address: xibaomin@smu.edu.cn.
  • 6 Guangdong Provincial Key Laboratory of New Drug Screening, Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, PR China. Electronic address: li75lin@smu.edu.cn.
PMID: 34971588 DOI: 10.1016/j.bcp.2021.114901
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.

Keywords

HIV-1 latency; Latency-reversing agents; Positive transcription elongation factor b; Reactivation; Shock and kill.

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