Research press release


Nature Communications

Medical research: A path towards better Alzheimer's drugs



今回、Douglas Johnsonたちは、化学プロテオミクスという手法を用いて、BACE1阻害剤のうちの1種類に標的外作用があり、BACE1に類似したタンパク質であるカテプシンDも阻害してしまうことを明らかにした。また、Johnsonたちは、培養ヒト細胞で測定されたカテプシンDの阻害と動物モデルで観察されたBACE1阻害剤を原因とする眼の副作用とが強く関連していることを明らかにした。さらに、Johnsonたちは、いくつかの既知のBACE1阻害剤のスクリーニングを行って、眼に副作用を起こさない特定の化合物を同定した。


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.

doi: 10.1038/ncomms13042

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