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Nat Commun2025;17(1):364.December 4, 2025Journal Article

Discovery of a small molecule TLR3 agonist adjuvant.

Branden Lee1, Danica Dong1, Etsuro Nanishi1,2, John Mark Awad1,2,3, Kimia Z Abedi1, Yoshine Saito1, Francesco Borriello1,4, Soumik Barman1,2, Byron Brook1,2, Aisling Kelly1, Manisha Menon1, Constance Marques-Mourlet1, Maansi V Gupta1, Ida Lister1, Chiwoo Oh1,2, Kevin Lyskawa1, Morgan Goetz1,2, Kristina Walker1, Wing Ki Cheng1, Spencer E Brightman1, Pankaj Sharma1, Timothy R O'Meara1, Katherine Chew1, Daniel Vieira1, Kevin Ryff1, Cali Sweitzer1, Sanya Thomas1,2, Simon D van Haren1,2, Matthew Pettengill1,2,5, Hyuk-Soo Seo6,7, Sirano Dhe-Paganon6,7, Wei Zhang3, Ofer Levy1,2,8, David J Dowling9,10
1Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA.
2Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
3Center for Green Chemistry and Department of Chemistry, University of Massachusetts Boston, Boston, MA, USA.
4Generate Biomedicines, Somerville, MA, USA.
5Department of Pathology and Genomic Medicine, Thomas Jefferson University, Philadelphia, PA, USA.
6Dana-Farber Cancer Institute, Boston, MA, USA.
7Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
8Broad Institute of MIT & Harvard, Cambridge, MA, USA.
9Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. David.Dowling@childrens.harvard.edu.
10Department of Pediatrics, Harvard Medical School, Boston, MA, USA. David.Dowling@childrens.harvard.edu.
PubMed PMC DOI PDF

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…

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