Carnitine is a pharmacological allosteric chaperone of the human lysosomal <i>α</i>-glucosidase

Pompe disease is an inherited metabolic disorder due to the deficiency of the lysosomal acid <i>α</i>-glucosidase (GAA). The only approved treatment is enzyme replacement therapy with the recombinant enzyme (rhGAA). Further approaches like pharmacological chaperone therapy, based on the stabilising effect induced by small molecules on the target enzyme, could be a promising strategy. However, most known chaperones could be limited by their potential inhibitory effects on patient’s enzymes. Here we report on the discovery of novel chaperones for rhGAA, L- and D-carnitine, and the related compound acetyl-D-carnitine. These drugs stabilise the enzyme at pH and temperature without inhibiting the activity and acted synergistically with active-site directed pharmacological chaperones. Remarkably, they enhanced by 4-fold the acid <i>α</i>-glucosidase activity in fibroblasts from three Pompe patients with added rhGAA. This synergistic effect of L-carnitine and rhGAA has the potential to be translated into improved therapeutic efficacy of ERT in Pompe disease.庞贝病（Pompe disease）是一种遗传性代谢紊乱疾病，由溶酶体酸性α-葡萄糖苷酶（GAA）缺乏引发。目前唯一获批的治疗方案为采用重组酶（rhGAA）的酶替代疗法（ERT）。基于小分子对靶酶的稳定作用所开发的药物伴侣疗法等其他策略，有望成为颇具前景的治疗手段。然而，多数已知的伴侣分子受限于其对患者体内酶的潜在抑制作用。本研究报道了针对rhGAA的新型伴侣分子——L-肉碱、D-肉碱及其相关化合物乙酰-D-肉碱的发现。上述药物可在特定pH值与温度条件下稳定酶活性，且不会抑制其催化功能，同时可与靶向活性位点的药物伴侣分子发挥协同作用。值得注意的是，在添加rhGAA的前提下，它们可将3名庞贝病患者成纤维细胞中的酸性α-葡萄糖苷酶活性提升4倍。L-肉碱与rhGAA的这种协同效应，有望转化为提升庞贝病患者酶替代疗法治疗效果的临床应用方案。