Abstract
Toxoplasmosis, caused by Toxoplasma gondii (T. gondii), is a serious zoonotic parasitic disease. We previously found that Lycosin-I exhibited anti-T. gondii activity, but its serum stability was not good enough. In this study, we aimed to improve the stability and activity of Lycosin-I through fatty acid chain modification, so as to find a better anti-T. gondii drug candidate. The α/ε-amino residues of different lysine residues of Lycosin-I were covalently coupled with lauric acid to obtain eight lipopeptides, namely L-C(12), L-C(12)-1, L-C(12)-2, L-C(12)-3, L-C(12)-4, L-C(12)-5, L-C(12)-6, and L-C(12)-7. Among these eight lipopeptides, L-C(12) showed the best activity against T. gondii in vitro in a trypan blue assay. We then conjugated a shorter length fatty chain, aminocaproic acid, at the same modification site of L-C(12), namely L-an. The anti-T. gondii effects of Lycosin-I, L-C(12) and L-an were evaluated via an invasion assay, proliferation assay and plaque assay in vitro. A mouse model acutely infected with T. gondii tachyzoites was established to evaluate their efficacy in vivo. The serum stability of L-C(12) and L-an was improved, and they showed comparable or even better activity than Lycosin-I did in inhibiting the invasion and proliferation of tachyzoites. L-an effectively prolonged the survival time of mice acutely infected with T. gondii. These results suggest that appropriate fatty acid chain modification can improve serum stability and enhance anti-T. gondii effect of Lycosin-I. The lipopeptide derivatives of Lycosin-I have potential as a novel anti-T. gondii drug candidate.