PVP-037

**PVP-037** is a novel small-molecule imidazopyrimidine immunomodulator identified through precision screening in primary human peripheral blood mononuclear cells (PBMCs) as a potent Toll-like receptor 7/8 (TLR7/8) agonist adjuvant. Developed by the Precision Vaccines Program at Boston Children's Hospital, it induces broad cytokine and chemokine production, including TNF, IFNγ, IL-1β, IL-6, IL-12p70, GM-CSF, IL-10, and CCL3 (MIP1α), at concentrations ≥1 μM, with peak TNF induction comparable to R848 at ≥11 μM, while showing no activity in THP-1 monocytic cell lines. Its mechanism involves TLR7/8-dependent NF-k B activation, confirmed by antagonist blockade and knockout studies, promoting Th1-skewed humoral responses (elevated IgG2c) against influenza (rHA, Flublok) and SARS-CoV-2 antigens in mice, including aged models, with enhanced potency and adjuvanticity upon structural optimization to analogs like PVP-037.1 and PVP-037.2. PVP-037 synergizes with oil-in-water emulsions (e.g., squalene-based) for stable nanoformulations, improving incorporation, reducing cytotoxicity, and boosting innate responses in dendritic cells and macrophages.[1][2][4][5]