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-_B 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.
Author Info: (1) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. (2) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. (3) Precision Vaccines Pro
Author Info: (1) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. (2) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. (3) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. Department of Pediatrics, Harvard Medical School, Boston, MA, USA. (4) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. Department of Pediatrics, Harvard Medical School, Boston, MA, USA. Center for Green Chemistry and Department of Chemistry, University of Massachusetts Boston, Boston, MA, USA. (5) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. (6) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. (7) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. Generate Biomedicines, Somerville, MA, USA. (8) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. Department of Pediatrics, Harvard Medical School, Boston, MA, USA. (9) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. Department of Pediatrics, Harvard Medical School, Boston, MA, USA. (10) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. (11) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. (12) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. (13) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. (14) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. (15) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. Department of Pediatrics, Harvard Medical School, Boston, MA, USA. (16) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. (17) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. Department of Pediatrics, Harvard Medical School, Boston, MA, USA. (18) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. (19) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. (20) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. (21) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. (22) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. (23) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. (24) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. (25) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. (26) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. (27) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. Department of Pediatrics, Harvard Medical School, Boston, MA, USA. (28) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. Department of Pediatrics, Harvard Medical School, Boston, MA, USA. (29) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. Department of Pediatrics, Harvard Medical School, Boston, MA, USA. Department of Pathology and Genomic Medicine, Thomas Jefferson University, Philadelphia, PA, USA. (30) Dana-Farber Cancer Institute, Boston, MA, USA. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. (31) Dana-Farber Cancer Institute, Boston, MA, USA. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. (32) Center for Green Chemistry and Department of Chemistry, University of Massachusetts Boston, Boston, MA, USA. (33) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. Department of Pediatrics, Harvard Medical School, Boston, MA, USA. Broad Institute of MIT & Harvard, Cambridge, MA, USA. (34) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. David.Dowling@childrens.harvard.edu. Department of Pediatrics, Harvard Medical School, Boston, MA, USA. David.Dowling@childrens.harvard.edu.
