Desmuramylpeptide, a NOD2 agonist, enhanced immune response and parasite clearance in Leishmania donovani infection.

Introduction: Visceral leishmaniasis is a life-threatening infectious disease caused by the intracellular protozoan Leishmania, where interactions between the parasite and the host's intracellular components play a crucial role in tracking the incursion of infection. Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) plays a critical role in regulating inflammation and eliciting a defensive immune response to the pathogen. Consequently, we aimed to explore the role of a desmuramylpeptide (NOD2 agonist) in visceral leishmaniaisis caused by Leishmania donovani.

Methodology: In this study, wedescribe the multistep solution-phase synthesis of a potent desmuramylpeptide (Compound 6) derived from trans-ferulic acid. This compound was subsequently evaluated for its in vitro biological activities against Leishmania donovani.

Results: Compound 6 demonstrated potent in vitro activity against L. donovani parasites (promastigote and amastigote forms) leading to successful clearance of parasites. Furthermore, it exhibited immunostimulatory effects by enhancing reactive oxygen species and nitric oxide production while showing moderate cytotoxicity against RAW 264.7 macrophages and HeLa cells. Notably, Compound 6 was more effective than muramyl dipeptide in promoting parasite clearance and eliciting robust immunomodulatory response.

Conclusion: Overall, the study highlights NOD2 as a critical mediator of immune modulation during Leishmania infection, suggesting its potential as a pharmacological target for host-directed immune intervention.