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<p>All clinically approved PARP1 inhibitors (PARPi) share NAD<sup>+</sup>-mimetic scaffolds, limiting structural diversity and hindering the discovery of next-generation agents. Their therapeutic potency depends on PARP1 trapping, a dynamic process that remains difficult to quantify, preventing the establishment of high-throughput screening (HTS) strategies. Here, we present a rapid and high-throughput surface-enhanced Raman scattering (SERS) biosensor for direct detection of PARP1 trapping at the molecular level. The biosensor reconstitutes the PARP1/HPF1–DNA complex on a magnetically active SERS nanoprobe, where NAD<sup>+</sup> binding triggers dissociation (signal-off), while PARPi competitively stabilize the complex (signal-on). Molecules sustaining SERS signals are identified as potential trapping-enhancing modulators. This biosensor accurately reproduced the trapping profiles of eight approved PARPi and, through screening of four compound libraries, revealed Oritavancin diphosphate as a novel non–NAD<sup>+</sup>-mimetic PARP1 trapping-enhancing modulator, validated in both cell-free and cellular contexts. This SERS-based PARP1 biosensor thus provides a sensitive, rapid, and cost-efficient optical strategy for high-throughput discovery of PARP1-targeted modulators and other macromolecular interaction-based therapeutics.</p> Graphical abstract <p></p>

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A SERS-based biosensor for optical monitoring of PARP1 trapping dynamics and high-throughput screening of modulators

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月15日

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  • Shizhi Xu,
  • Ziming Wang,
  • Baizhi Li,
  • Jiayu Wang,
  • Shai Fang,
  • Wei Huang,
  • Zhiyi Liu,
  • Hongrui Li,
  • Jinbao Xiang,
  • Shuping Xu,
  • Chongyang Liang

摘要

All clinically approved PARP1 inhibitors (PARPi) share NAD+-mimetic scaffolds, limiting structural diversity and hindering the discovery of next-generation agents. Their therapeutic potency depends on PARP1 trapping, a dynamic process that remains difficult to quantify, preventing the establishment of high-throughput screening (HTS) strategies. Here, we present a rapid and high-throughput surface-enhanced Raman scattering (SERS) biosensor for direct detection of PARP1 trapping at the molecular level. The biosensor reconstitutes the PARP1/HPF1–DNA complex on a magnetically active SERS nanoprobe, where NAD+ binding triggers dissociation (signal-off), while PARPi competitively stabilize the complex (signal-on). Molecules sustaining SERS signals are identified as potential trapping-enhancing modulators. This biosensor accurately reproduced the trapping profiles of eight approved PARPi and, through screening of four compound libraries, revealed Oritavancin diphosphate as a novel non–NAD+-mimetic PARP1 trapping-enhancing modulator, validated in both cell-free and cellular contexts. This SERS-based PARP1 biosensor thus provides a sensitive, rapid, and cost-efficient optical strategy for high-throughput discovery of PARP1-targeted modulators and other macromolecular interaction-based therapeutics.

Graphical abstract