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<p>Monoclonal antibody-based immune checkpoint inhibitors, which have brought breakthrough effects in cancer treatments, are expected to assist in the treatment of viral diseases. However, antibody therapies may cause immune-related side effects, such as inflammation and pneumonia, due to cytokine storms. Small-molecule PD-1/PD-L1 inhibitors are an alternative to monoclonal antibody-based therapeutics. We have identified a novel small-molecule PD-1/PD-L1 inhibitor having a functional group (disulfide group), namely compound <b>2</b> (molecular weight: 456.6), from our library of sulfur-containing protein–protein interaction inhibitor compounds. Compound <b>2</b> selectively bound to PD-L1 over PD-1, with the dissociation rate constant (K<sub>D</sub>) of 77.60 ± 4.44&#xa0;nM (obtained by affinity analysis) and showed promising T cell activation recovery. A molecular docking simulation study between <b>2</b> and PD-L1 suggested that <b>2</b> binds to PD-L1 in a binding mode different from those of other small-molecule PD-L1/PD-1 inhibitors. Notably, oral administration of <b>2</b> to mice pre-infected with influenza A virus (A/NWS/33, H1N1 subtype) caused a significant increase in the neutralizing antibody titers, as well as recovery from influenza-induced pneumonia. Overall, <b>2</b> provides insight for the development of therapeutic drugs against early viral infections, with both virus titer-reducing and antibody titer-boosting effects. Moreover, <b>2</b> is widely used as a rubber peptizing agent in the production process of tires and other rubber products. Our findings may provide useful information for investigating its influence on living organisms.</p>

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Discovery of novel disulfide-containing PD-1/PD-L1 inhibitor with in vivo influenza therapeutic efficacy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月26日

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  • Yoshiyuki Hirata,
  • Kyoko Hayashi,
  • Takuma Kato,
  • Yasuo Nagaoka,
  • Mitsunobu Doi,
  • Shinichi Uesato

摘要

Monoclonal antibody-based immune checkpoint inhibitors, which have brought breakthrough effects in cancer treatments, are expected to assist in the treatment of viral diseases. However, antibody therapies may cause immune-related side effects, such as inflammation and pneumonia, due to cytokine storms. Small-molecule PD-1/PD-L1 inhibitors are an alternative to monoclonal antibody-based therapeutics. We have identified a novel small-molecule PD-1/PD-L1 inhibitor having a functional group (disulfide group), namely compound 2 (molecular weight: 456.6), from our library of sulfur-containing protein–protein interaction inhibitor compounds. Compound 2 selectively bound to PD-L1 over PD-1, with the dissociation rate constant (KD) of 77.60 ± 4.44 nM (obtained by affinity analysis) and showed promising T cell activation recovery. A molecular docking simulation study between 2 and PD-L1 suggested that 2 binds to PD-L1 in a binding mode different from those of other small-molecule PD-L1/PD-1 inhibitors. Notably, oral administration of 2 to mice pre-infected with influenza A virus (A/NWS/33, H1N1 subtype) caused a significant increase in the neutralizing antibody titers, as well as recovery from influenza-induced pneumonia. Overall, 2 provides insight for the development of therapeutic drugs against early viral infections, with both virus titer-reducing and antibody titer-boosting effects. Moreover, 2 is widely used as a rubber peptizing agent in the production process of tires and other rubber products. Our findings may provide useful information for investigating its influence on living organisms.