A new strategy that could be used to improve a class of Alzheimer’s drugs so that they cause fewer side effects is reported in Nature Communications this week. The paper explains why drugs known as BACE1 inhibitors cause side effects in the eyes, and also describes a test that predicts whether ocular side effects are likely to occur in animals.
The enzyme beta-secretase (BACE1) is involved in the formation of amyloid beta, the protein known to accumulate in brains of patients with Alzheimer’s disease. Drugs that inhibit BACE1 are currently developed in the hope that they will slow down disease progression. However, several such drug candidates have failed in clinical trials in part due to side effects in which toxic compounds were found to accumulate in the eyes.
Douglas Johnson and colleagues used a technique called chemoproteomics to show that one of their BACE1 inhibitors inadvertently also inhibits a related protein, known as cathepsin D. The authors go on to show that inhibition of cathepsin D, measured in cultured human cells, is strongly associated with ocular side effects caused by BACE1 inhibitors observed in animal models. Through screening several known BACE1 inhibitors, the authors also identify specific compounds that do not cause side effects on the eye.
The authors suggest these data will aid the development of drugs with fewer side effects for treating Alzheimer’s disease.