Anti-Toxoplasma gondii Effect of Lipopeptide Derivatives of Lycosin-I

Abstract

Abstract Conclusions: Appropriate fatty acid modification can improve the serum stability of Lycosin-I and enhance the in vivo anti-Toxoplasma gondii effect of Lycosin-I. These results suggest that the lipopeptide derivative of Lycosin-Ⅰ have the potential as a novel drug candidate of anti- T. gondii. Background: Toxoplasmosis, caused by Toxoplasma gondii (T. gondii), is a serious zoonotic parasitic disease. Due to the side effects and drug resistance of clinical medications for toxoplasmosis, it is urgent to develop new anti-toxoplasmosis drugs. In our previous study, we found that Lycosin-I exhibited anti- T. gondii activity both in vitro and in vivo, but its serum stability in vivo was not good enough. In this study, we aimed to improve the stability and activity of Lycosin-I through fatty acid modification, so as to find a better anti- T. gondii targeting drug candidate. Methods: The α/ε-amino radicals of different lysine residues of Lycosin-Ⅰ were covalently coupled with lauric acid to obtain eight lipopeptides, namely L-C12, L-C12-1, L-C12-2, L-C12-3, L-C12-4, L-C12-5, L-C12-6, L-C12-7. The anti-T. gondii activity of these lipopeptides in vitro was screened using Trypan blue assay. The anti-T. gondii effects of Lycosin-I, L-C12 and L-an were evaluated by invasion assay, proliferation assay and plaque assay in vitro. A mouse model acutely infected with T. gondii was established to evaluate their efficacy in vivo. Results: Among these eight lipopeptides, L-C12 showed the best activity against T. gondii in vitro. We then conjugated a shorter length fatty chain, aminocaproic acid, at the same modification site of L-C12, namely L-an. The serum stability of L-C12 and L-an was improved, and they showed comparable or even better activity than Lycosin-I in inhibiting the invasion, proliferation and migration of T. gondii tachyzoites. L-an effectively prolonged the survival time of mice acutely infected with T. gondii.