Computer-aided design of short peptide ligands targeting N-formyl peptide MT-ND6: potential application in treating severe inflammatory diseases

Abstract

High levels of N-formyl peptide MT-ND6 in serum are significantly associated with disease severity and mortality in critically ill patients, including those with sepsis and severe acute pancreatitis. Selective removal of MT-ND6 in blood to reduce inflammation and tissue damage may be an important immunomodulatory strategy. In the present study, we designed peptide ligands that could bind to MT-ND6 with high affinity. Molecular docking, MD, and MM-PBSA were used to investigate the affinity and stability of peptide/MT-ND6 complexes. To examine the usefulness of affinity ligands for MT-ND6, three peptides were fixed on polystyrene–divinylbenzene (PS) microspheres and adsorption capacity was studied. Adsorption tests showed the adsorbent PS-RF had the higher adsorption percentage (85.42 ± 1.74%) for MT-ND6 than PS microspheres (44.42 ± 2.73%). Moreover, the maximum adsorption capacity of PS-RF reached 6042.96 pg g⁻¹. PS-based immunosorbents loaded with different peptides have no hemolytic effect, no significant effect on blood cell composition and blood coagulation activity, and no cytotoxicity, indicating good biocompatibility. In conclusion, the ligand RF screened by computer-aided molecular design exhibits a stronger affinity to MT-ND6 and it can significantly enhance the adsorption efficiency of MT-ND6 in serum. The PS-RF immunosorbent has great potential for the removal of MT-ND6 by hemoperfusion. The screening process of peptide ligands also provides a basis for the further design and optimization of affinity ligands for MT-ND6.