Abstract:
Synthetic antibodies hold great promise in combating diseases, diagnosis, and a wide range of biomedical
applications. However, designing a therapeutically amenable, synthetic antibody that can arrest the aggregation
of amyloid-b (Ab) remains challenging. Here, we report a flexible, hairpin-like synthetic paratope (SP1, 2 kDa),
which prevents the aggregation of Ab monomers and reverses the preformed amyloid fibril to a non-toxic
species. Structural and biophysical studies further allowed dissecting the mode and affinity of molecular
recognition events between SP1 and Ab. Subsequently, SP1 reduces Ab-induced neurotoxicity, neuronal
apoptosis, and ROS-mediated oxidative damage in human neuroblastoma cells (SH-SY5Y). The non-toxic
nature of SP1 and its ability to ameliorate hippocampal neurodegeneration in a rat model of AD demonstrate its
therapeutic potential. This paratope engineering module could readily implement discoveries of cost-effective
molecular probes to nurture the basic principles of protein misfolding, thus combating related diseases.
