A novel peptide antagonist for SATB1 in the immune response to Leishmania infection

Peptide-based therapies are emerging as powerful tools in the treatment of inflammatory and infectious diseases, offering high specificity, low toxicity, and minimal side effects. In this study, we identify Special AT-rich Binding Protein-1 (SATB1) as a novel immunotherapy target for cutaneous leishmaniasis (CL). As a global chromatin regulator, SATB1 is initially confined to the cytoplasm, but as infection progresses, it translocates to the nucleus, triggering Basic Helix-Loop-Helix Family Member E40 (Bhlehe40) - mediated Granulocyte-macrophage colony-stimulating factor (GM-CSF) production and inflammatory responses involving IL-6, IL-17, IL-23, and Sphingosine-1-phosphate (S1P). To restore immune balance, we strategically disrupt conserved residues Lysine (Lys) 29, Arginine (Arg) 32, Glutamic acid (Gln) 34, and Asparagine (Asn) 36 within SATB1's nuclear localization signal (NLS) using machine learning (ML) based peptide design approaches. Structural predictions, motif identification, and peptide library screening led to the selection of three peptide candidates (P1, P2, and P3) based on binding affinity and molecular interactions. Experimental validation identified P3 as the most effective peptide, successfully mitigating infection and re-establishing immune homeostasis in vitro and in vivo. This research underscores the potential of peptide-based therapeutics in developing targeted treatments for cutaneous leishmaniasis and other immune-related disorders.