2. Academic Validation
  3. Rational Design and Identification of Highly Selective TLR8 Agonists as Potent HIV-1 Latency Reversal Agents

Rational Design and Identification of Highly Selective TLR8 Agonists as Potent HIV-1 Latency Reversal Agents

  • J Med Chem. 2026 Mar 12;69(5):5405-5424. doi: 10.1021/acs.jmedchem.5c02319.
Zhisong Wang 1 2,  Yangyang Li 3 4 5,  Jie Wang 2,  Shuhao Sun 1,  Yixuan Zhang 1,  Linqi Zhang 5 6,  Xuebin Liao 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Molecular Oncology, School of Pharmaceutical Sciences, Tsinghua-Peking Center for Life Science, Tsinghua University, Beijing 100084, China.
  • 2 Synvac Biosciences Co.,Ltd, Beijing 102206, China.
  • 3 The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, School of Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 611731, China.
  • 4 Sichuan Medical Laboratory Clinical Medical Research Center, Sichuan Provincial People's Hospital, Chengdu 611731, China.
  • 5 Comprehensive AIDS Research Center, Pandemic Research Alliance Unit, Center for Infection Biology, School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China.
  • 6 Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China.
PMID: 41739651 DOI: 10.1021/acs.jmedchem.5c02319
Abstract

Highly active antiretroviral therapy (HAART) for HIV-1 Infection suppresses but does not cure the disease due to persistent latent viral reservoirs. The "shock and kill" strategy aims to eradicate these reservoirs completely. In exploring the role of TLR8 activation in this context, extensive efforts have been devoted to identify compound 23a, a potent and selective TLR8 Agonist with strong agonistic activity (EC50 = 19 nM) and high selectivity (∼1300-fold) over TLR7. Notably, compound 23a exhibits potent reactivation of latent HIV-1 reservoirs in both infected cell lines and primary PBMCs from HAART-treated patients, demonstrating superior efficacy compared to the TLR7 Agonist GS-9620 (NCT05281510). Additionally, 23a (SV-128) effectively activated innate cytolytic effectors, including natural killer (NK) cells, which targeted HIV-infected CD4+ T cells. These findings demonstrate the promising therapeutic potential of TLR8 agonists for HIV-1 eradication, combining both "shock" (latency reversal) and "kill" (immune-mediated clearance) mechanisms.

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