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<p>HIV-1 protease (PR) is initially synthesized as part of the Gag-Pol polyprotein precursor, which undergoes temporospatially regulated autoprocessing to liberate mature PR. The free mature enzyme is the target of currently available protease inhibitors (PIs). To explore alternative therapeutic strategies, we developed a cell-based high-throughput screening (HTS) platform targeting precursor autoprocessing, screened approximately 320,000 small molecules, and identified 27 compounds that partially suppress precursor autoprocessing. A highly sensitive infectivity assay confirmed that several compounds inhibited viral infectivity in a dose-dependent manner, with EC<sub>50</sub> values in the low micromolar range. Notably, hit compound C7 exhibited comparable potency against both wild-type and drug-resistant HIV strains, suggesting a novel mechanism of action. An initial structure–activity relationship (SAR) analysis via analog-by-catalog suggested that antiviral activity is influenced by specific chemical groups. This study provides proof of concept for an innovative drug discovery approach targeting HIV-1 PR autoprocessing as a potential strategy to combat drug resistance.</p>

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High-throughput screening and characterization of novel inhibitors targeting HIV-1 protease precursor autoprocessing

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年10月9日

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  • Ryan H. Jeep,
  • Liangqun Huang,
  • Tram A. Ngo,
  • Fu-Yue Zeng,
  • James Boehlke,
  • Luke Bennett,
  • Stanton Ashman,
  • Ian Pass,
  • Thomas D. Y. Chung,
  • Chaoping Chen

摘要

HIV-1 protease (PR) is initially synthesized as part of the Gag-Pol polyprotein precursor, which undergoes temporospatially regulated autoprocessing to liberate mature PR. The free mature enzyme is the target of currently available protease inhibitors (PIs). To explore alternative therapeutic strategies, we developed a cell-based high-throughput screening (HTS) platform targeting precursor autoprocessing, screened approximately 320,000 small molecules, and identified 27 compounds that partially suppress precursor autoprocessing. A highly sensitive infectivity assay confirmed that several compounds inhibited viral infectivity in a dose-dependent manner, with EC50 values in the low micromolar range. Notably, hit compound C7 exhibited comparable potency against both wild-type and drug-resistant HIV strains, suggesting a novel mechanism of action. An initial structure–activity relationship (SAR) analysis via analog-by-catalog suggested that antiviral activity is influenced by specific chemical groups. This study provides proof of concept for an innovative drug discovery approach targeting HIV-1 PR autoprocessing as a potential strategy to combat drug resistance.