Document Type
Article
Publication Date
12-4-2025
Abstract
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.
Recommended Citation
Lee, Branden; Dong, Danica; Nanishi, Etsuro; Awad, John Mark; Abedi, Kimia; Saito, Yoshine; Borriello, Francesco; Barman, Soumik; Brook, Byron; Kelly, Aisling; Menon, Manisha; Marques-Mourlet, Constance; Gupta, Maansi; Lister, Ida; Oh, Chiwoo; Lyskawa, Kevin; Goetz, Morgan; Walker, Kristina; Cheng, Wing Ki; Brightman, Spencer; Sharma, Pankaj; O'Meara, Timothy; Chew, Katherine; Vieira, Daniel; Ryff, Kevin; Sweitzer, Cali; Thomas, Sanya; van Haren, Simon; Pettengill, Matthew; Seo, Hyuk-Soo; Dhe-Paganon, Sirano; Zhang, Wei; Levy, Ofer; and Dowling, David, "Discovery of a Small Molecule TLR3 Agonist Adjuvant" (2025). Department of Pathology, Anatomy, and Cell Biology Faculty Papers. Paper 477.
https://jdc.jefferson.edu/pacbfp/477
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
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PubMed ID
41339634
Language
English
Comments
This article is the author’s final published version in Nature Communications, Volume 17, Issue 1, 2026, Article number 364.
The published version is available at https://doi.org/10.1038/s41467-025-66878-3. Copyright © The Author(s) 2025.