Abstract
Cutaneous leishmaniasis (CL) is regulated by cytokine reciprocity, the dynamic balance between pro- and anti-inflammatory cytokines that determines disease outcomes. The Interleukin-12 (IL-12) and Interleukin-10 (IL-10) axis governs the type 1 and type 2 T helper cell (Th1/Th2) immune response, where dysregulation favors parasite persistence. Src homology 2 domain-containing protein tyrosine phosphatase (SHP-1) modulates this axis to promote Leishmania survival. Using an artificial intelligence-driven approach, therapeutic peptides targeting SHP-1 were designed and evaluated in Leishmania major (L. major) infection model. Among these, Peptide A (PepA) exhibited potent SHP-1 inhibition, enhanced nuclear factor of activated T cells 5 (NFAT5) translocation, and increased nitric oxide (NO) production through inducible nitric oxide synthase (iNOS/Nos2) upregulation. PepA also induced M1 (classically activated) macrophages, restored IL-12, suppressed IL-10 expression, and significantly reduced parasite load. These findings identify PepA ("LeishPepThera") as a promising immunotherapeutic candidate that rebalances host immune signaling to promote parasite clearance in CL.