Abstract

Background/Objectives: Autism spectrum disorder (ASD) is a group of developmental disorders featured by social dysfunction, for which there still lacks effective treatments. Our previous study demonstrated that XAV939, a tankyrase inhibitor, could alleviate social dysfunction in two ASD mouse models via suppressing Wnt and glycolytic signaling. However, its further application is limited by poor brain–blood barrier penetration and low bioavailability. Methods: XAV939 was structurally optimized by esterification. The effects of XAV939-derivatives on Wnt/glycolysis were assessed by Western blotting, Topflash luciferase assay, lactate levels and the extracellular acidification rate. Social behaviors were evaluated by a three-chamber test, a resident–intruder test and ultrasonic vocalization. Biomimetic brain targeting was achieved by neuron-astrocyte hybrid cell membrane encapsulation. Periphery toxicities were examined by biochemical and histological analysis. Results: Three esterified XAV939 were synthesized. Data from both 293FT cells and primary Shank3b-/- neurons revealed that an alkyl ester prodrug of XAV939 (named XAV939-L1) exhibited dual inhibition of Wnt/glycolysis. Intravenous injection of XAV939-L1 effectively improved the social function of Shank3b-/- mice but showed hepatic side effects. Further, we made brain-targeting XAV939-L1 (XAV939-L1-BT) by neuron–astrocyte hybrid cell membrane encapsulation, which greatly enhanced the accumulation of XAV939-L1-BT in the brain and reduced its distribution in peripheral tissues (liver and intestine). At a half-dose of XAV939-L1, XAV939-L1-BT exhibited significant social improvement effects without obvious hepatic and intestinal toxicity. Conclusions: Our data demonstrated an esterified XAV939 and its biomimetic brain-targeted formula as a potential drug candidate for treating ASD-associated social dysfunction.

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