Synthesis, Antimalarial Activity and Molecular Dynamics Studies of Pipecolisporin: A Novel Cyclic Hexapeptide with Potent Therapeutic Potential.

Malaria, caused by species and transmitted by mosquitoes, continues to pose a significant global health threat. Pipecolisporin, a cyclic hexapeptide isolated from , has emerged as a promising antimalarial candidate due to its potent biological activity and stability. This study explores the synthesis, antimalarial activity, and computational studies of pipecolisporin, aiming to better understand its therapeutic potential. The peptide was successfully synthesized using Fmoc-based solid-phase peptide synthesis (SPPS) followed by cyclization in solution. The purified compound was characterized using HPLC and mass spectrometry, confirming a molecular ion peak at / [M + H] 692.4131, which matched the calculated mass. Structural verification through H- and C-NMR demonstrated strong alignment with the natural product. Pipecolisporin exhibited significant antimalarial activity with an IC of 26.0 ± 8.49 nM, highlighting its efficacy. In addition to the experimental synthesis, computational studies were conducted to analyze the interaction of pipecolisporin with key malaria-related enzymes, such as dihydrofolate reductase, plasmepsin V, and lactate dehydrogenase. These combined experimental and computational insights into pipecolisporin emphasize the importance of hydrophobic interactions, particularly in membrane penetration and receptor binding, for its antimalarial efficacy. Pipecolisporin represents a promising lead for future antimalarial drug development, with its efficacy, stability, and binding characteristics laying a solid foundation for ongoing research.