Chemical degradation of Human p38-MAPK reveals it as a potential host target to combat parasitic infections by Leishmania donovani and Plasmodium falciparum

The interplay between host and Parasite determines Parasite burden and disease outcome. Parasite exploits host signaling pathways like p38-MAPK for its survival and pathogenesis. Here we have used NR-7h, a proteolysis-targeting chimera (PROTAC) targeting human p38-MAPK to assess p38-MAPK's role in Leishmania donovani and Plasmodium falciparum Infection in their respective host cells. NR-7h degrades host p38-MAPK in a time- and dose-dependent manner. Degradation of host p38-MAPK by NR-7h reduces Parasite load in host cells dose-dependently, implicating the role of p38-MAPK in Parasite survival. During Leishmania infection, the modulation of cytokine profiling and oxidative burst upon NR-7h mediated degradation of host p38-MAPK is further correlated with Parasite death. The effect of host p38-MAPK degradation by NR-7h with Amphotericin B enhances the efficacy of parasite-directed therapy. For Plasmodium infection, growth inhibition and invasion assays reveal impaired growth and merozoite invasion, suggesting that host p38-MAPK signaling contributes to both Parasite invasion and intraerythrocytic development. This study underscores the importance of host p38-MAPK for L. donovani and P. falciparum progression and highlights NR-7h's potential in antiparasitic therapy by targeting this pathway.