Discovery of a small molecule TLR3 agonist adjuvant
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.
Authors
- Aisling Kelly (ORCID: https://orcid.org/0009-0006-7872-6719)
- Constance Marques-Mourlet
- Yoshine Saito (ORCID: https://orcid.org/0000-0002-5047-6627)
- Sanya Thomas (ORCID: https://orcid.org/0000-0003-3648-9461)
- Simon D. van Haren (ORCID: https://orcid.org/0000-0002-1791-0161)
- Daniel Vieira (ORCID: https://orcid.org/0000-0003-0914-9920)
- Katherine Chew (ORCID: https://orcid.org/0000-0003-4085-0643)
- David J. Dowling (ORCID: https://orcid.org/0000-0003-1095-6156)
- Pankaj Sharma (ORCID: https://orcid.org/0000-0002-9130-9235)
- Soumik Barman (ORCID: https://orcid.org/0000-0002-3641-2125)
- Timothy R. O’Meara (ORCID: https://orcid.org/0000-0002-3651-5167)
- Francesco Borriello (ORCID: https://orcid.org/0000-0001-9074-4828)
- Cali Sweitzer (ORCID: https://orcid.org/0000-0002-7941-215X)
- Sirano Dhe‐Paganon (ORCID: https://orcid.org/0000-0003-0824-5929)
- Danica Dong (ORCID: https://orcid.org/0000-0003-2180-6508)
- Spencer E. Brightman (ORCID: https://orcid.org/0000-0002-9930-7218)
- Manisha Menon (ORCID: https://orcid.org/0000-0002-7152-3752)
- Byron Brook (ORCID: https://orcid.org/0000-0003-3184-8285)
- Ofer Levy (ORCID: https://orcid.org/0000-0002-5859-1945)
- Branden Lee (ORCID: https://orcid.org/0000-0001-5294-9304)
- Wing Ki Cheng
- Hyuk‐Soo Seo (ORCID: https://orcid.org/0000-0003-0646-2102)
- Matthew Aaron Pettengill (ORCID: https://orcid.org/0000-0002-4579-0187)
- Etsuro Nanishi (ORCID: https://orcid.org/0000-0002-9957-7162)
- Kimia Abedi (ORCID: https://orcid.org/0009-0004-8574-8217)
- Kevin Ryff (ORCID: https://orcid.org/0009-0000-3112-0687)
- Wei Zhang (ORCID: https://orcid.org/0000-0002-6097-2763)
- Kristina Walker
- J. Awad (ORCID: https://orcid.org/0000-0002-1264-1847)
- Maansi V. Gupta (ORCID: https://orcid.org/0009-0009-2680-1555)
- I Nyoman Ehrich Lister
- Morgan Goetz
- Chiwoo Oh
- Kevin Lyskawa
Institutions
- Broad Institute (US)
- Boston University (US)
- Boston Children's Hospital (US)
- Harvard University (US)
- Thomas Jefferson University (US)
- University of Massachusetts Boston (US)
- Intarcia Therapeutics (United States) (US)
- Dana-Farber Cancer Institute (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-04
- DOI
- https://doi.org/10.1038/s41467-025-66878-3
- Primary Topic
- Immune Response and Inflammation
- Type
- article
- Field-Weighted Citation Impact
- 0.00