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<p>Pattern-recognition receptor (PRR) agonists are valuable agents across multiple medical applications, from vaccinology to immune-oncology. However, well-defined and potent small molecule agonists for many PRRs still await discovery and development. Screening of chemical libraries of ~200,000 small molecules for maturation of human monocytic cells by quantifying NF-κB activation and cell adherence was completed. From this screen, we selected a thiazole benzamide derivative, PVP-057, for its robust immunomodulatory properties, low toxicity profile, and concentration-dependent activity. In vitro investigation of pathway and receptor activation reveals that PVP-057 is a Toll-like receptor 3 (TLR3) agonist. As a single-component adjuvant, administered intramuscularly or intradermally to female mice, PVP-057 enhances long-term humoral immunogenicity of varicella-zoster virus glycoprotein E to levels comparable to those induced by the clinical grade standard benchmark adjuvant, AS01B, while concurrently inducing cell-mediated immunity. To demonstrate the large-scale and precise synthesis necessary for the efficient mass production of a small molecule agonist, a green chemistry approach was completed, devising a three-step, 24-hour synthesis scheme for PVP-057, with a reliable purity of ~98%. Featuring highly efficient and scalable synthesis, a distinct TLR3-dependent mechanism of action, and robust adjuvanticity, the PVP-057 pharmacophore has prophylactic and therapeutic potential.</p>

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Discovery of a small molecule TLR3 agonist adjuvant

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月4日

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  • Branden Lee,
  • Danica Dong,
  • Etsuro Nanishi,
  • John Mark Awad,
  • Kimia Z. Abedi,
  • Yoshine Saito,
  • Francesco Borriello,
  • Soumik Barman,
  • Byron Brook,
  • Aisling Kelly,
  • Manisha Menon,
  • Constance Marques-Mourlet,
  • Maansi V. Gupta,
  • Ida Lister,
  • Chiwoo Oh,
  • Kevin Lyskawa,
  • Morgan Goetz,
  • Kristina Walker,
  • Wing Ki Cheng,
  • Spencer E. Brightman,
  • Pankaj Sharma,
  • Timothy R. O’Meara,
  • Katherine Chew,
  • Daniel Vieira,
  • Kevin Ryff,
  • Cali Sweitzer,
  • Sanya Thomas,
  • Simon D. van Haren,
  • Matthew Pettengill,
  • Hyuk-Soo Seo,
  • Sirano Dhe-Paganon,
  • Wei Zhang,
  • Ofer Levy,
  • David J. Dowling

摘要

Pattern-recognition receptor (PRR) agonists are valuable agents across multiple medical applications, from vaccinology to immune-oncology. However, well-defined and potent small molecule agonists for many PRRs still await discovery and development. Screening of chemical libraries of ~200,000 small molecules for maturation of human monocytic cells by quantifying NF-κB activation and cell adherence was completed. From this screen, we selected a thiazole benzamide derivative, PVP-057, for its robust immunomodulatory properties, low toxicity profile, and concentration-dependent activity. In vitro investigation of pathway and receptor activation reveals that PVP-057 is a Toll-like receptor 3 (TLR3) agonist. As a single-component adjuvant, administered intramuscularly or intradermally to female mice, PVP-057 enhances long-term humoral immunogenicity of varicella-zoster virus glycoprotein E to levels comparable to those induced by the clinical grade standard benchmark adjuvant, AS01B, while concurrently inducing cell-mediated immunity. To demonstrate the large-scale and precise synthesis necessary for the efficient mass production of a small molecule agonist, a green chemistry approach was completed, devising a three-step, 24-hour synthesis scheme for PVP-057, with a reliable purity of ~98%. Featuring highly efficient and scalable synthesis, a distinct TLR3-dependent mechanism of action, and robust adjuvanticity, the PVP-057 pharmacophore has prophylactic and therapeutic potential.