Design, synthesis and Anti-Plasmodial activity of Mortiamide-Lugdunin conjugates

In this study, two linear and corresponding cyclic heptapeptide versions of mortiamide A-lugdunin hybrids were designed and synthesized by integrating an anti-malarial peptide epitope derived from Mortiamide A, combined with four residues known for their membrane interactions. Using this synthetic strategy, the sequence of mortiamide A was partly re-engineered with an epitope sequence of lugdunin along with an amino acid replacement using all-L and D/L configurations. Importantly, the re-engineered cyclic mortiamides with all-L (3) and D/L (4) configurations exhibited promising anti-malarial activities against the P. falciparum drug-sensitive TM4/8 strain with half-maximal inhibitory concentration (IC₅₀) values of 6.2 ± 0.5 and 4.8 ± 0.1 μM, respectively. Additionally, they exhibited anti-malarial activities against the P. falciparum multidrug-resistant V1/S strain with IC₅₀ values of 5.0 ± 2.6 and 3.7 ± 0.7 μM, respectively. Interestingly, a linear re-engineered mortiamide with D/L configuration (2) exhibited promising anti-malarial activities, surpassing those of the re-engineered cyclic mortiamides (3 and 4), against both the P. falciparum sensitive TM4/8 and multidrug-resistant V1/S strains with IC₅₀ values of 3.6 ± 0.5 and 2.8 ± 0.7 μM (IC₅₀ of Mortiamide A = 7.85 ± 0.97, 5.31 ± 0.24 μM against 3D7 and Dd2 strains) without any cytotoxicity at >100 µM. The presence of D/L forms in a linear structure significantly impacted the anti-malarial activity against both the P. falciparum sensitive TM4/8 strain and the multidrug-resistant V1/S strain.