Drug Development

Recent advancements in the understanding of the molecular pathophysiology of amyloid-β (Aβ) in Alzheimer's disease (AD) have identified soluble oligomers as the dominant toxic form of Aβ correlating with cognitive decline. These toxic oligomers have been observed to adopt a nonstandard secondary structure: α-sheet. SOBIN-01, has been specifically designed to target the α-sheet structure of toxic oligomers.

Using biolayer interferometry we determined the binding affinity of SOBIN-01 to the monomeric random coil, α-sheet, and β-sheet forms of Aβ. We then examined the efficacy of fluorescently labeled α-sheet Aβ uptake in vitro in cultured microglia and macrophage cells with SOBIN-01 treatment. Finally, we measured the in vivo effects of SOBIN-01 on Aβ plaque accumulation by treating 3-month-old Tg2576 AD mice for 12 months.

The biolayer interferometry studies demonstrated that SOBIN-01 binds tightly and preferentially to α-sheet oligomers over both random coil monomers and β-sheet protofibrils, with a 2.4x10⁴- and 1.2x10⁵-fold change, respectively. We observed enhanced phagocytosis of fluorescently labeled α-sheet Aβ in a dose-dependent manner from 0.1-10 μM SOBIN-01 in both microglia and macrophages, with a 1.9- and 3.4-fold change with 10 μM treatment, respectively. We then examined whether SOBIN-01 would have effects on Aβ accumulation in the Tg2576 AD mouse model and observed a significant reduction in the percent plaque area in the brains of SOBIN-01 treated animals.

SOBIN-01 is a highly specific peptide that targets the α-sheet conformation of Aβ and leads to enhanced phagocytosis by microglia and macrophage cells. In vivo SOBIN-01 demonstrated a significant reduction in plaque area in Tg2576 AD mice. Together, these data suggest that SOBIN-01 targets and stimulates the clearance of Aβ toxic oligomers.