Friend or foe: divergent immunomodulatory effects of metabolites derived from the virucidal zinc finger inhibitor SAMT-247

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Background Topical administration of SAMT-247, a mercaptobenzamide thioester zinc finger inhibitor targeting the HIV nucleocapsid Gag zinc finger protein, generates multiple metabolites in mucosal tissues, including Met-A, Met-B, Met-C, and Met-D. Prior studies established that SAMT-247, delivered either as a vaginal gel or via an intravaginal ring (IVR), synergizes with the ΔV1DNA/ALVAC-SIV/ΔV1gp120/alum vaccine regimen to markedly reduce vaginal SIV mac251 acquisition risk. This enhanced protection is associated with augmented protective mucosal immunity and reduced inflammatory responses that promote viral acquisition. Methods We performed in vivo characterization of SAMT-247 metabolite distribution in the vaginal compartment of macaques and evaluate the biological activity of individual metabolites using ex vivo rectal mucosal biopsies from vaccinated animals. Results High concentrations of Met-B, Met-C, and Met-D were detected in vaginal secretions, whereas vaginal tissues contained predominantly Met-D, low levels of Met-A, and no detectable Met-B or Met-C. Functionally, Met-D most closely recapitulated and reinforced the protective immune profile associated with SAMT-247, preserving or expanding IL-17 + NKp44 + innate lymphoid cells (ILCs) and CD107a + NKG2A + natural killer (NK) cells, increasing CD73 + ILCs, NK and dendritic cell as well as IL-10 + dendritic cell and monocyte populations, and reducing inflammatory TNF-α-producing myeloid subsets. Met-B and Met-C partially reproduced this profile, enhancing CD73 + NK/ILC populations and promoting anti-inflammatory myeloid responses, but with more limited effects on antiviral NK/ILC activity and attenuated NKp44 + ILC responses relative to Met-D. In contrast, Met-A, which lacks virucidal activity, failed to induce regulatory CD73 + and IL-10 + responses and diminished both protective IL-17 + NKp44 + ILCs and cytolytic CD107a + NKG2A + NK cells, consistent with inflammatory skewing. In vaccinated macaques receiving SAMT-247-releasing IVRs, plasma Met-A showed limited correlation with rectal mucosal immune responses, partially supporting the ex vivo findings. Conclusion We observed distinct immunomodulatory effects associated with different SAMT-247 metabolites. These findings may guide future delivery strategies that favor tissue-available Met-D while limiting Met-A accumulation. More broadly, this study underscores the importance of metabolite-specific analyses for defining the biological activity and mechanisms of action of therapeutic agents.

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