HMG-CoA reductase(HMGCR) protein is usually upregulated after statin(HMGCR inhibitor) treatment, which inevitably diminishes its therapeutic efficacy, provoking the need for higher doses associated with adverse effect...HMG-CoA reductase(HMGCR) protein is usually upregulated after statin(HMGCR inhibitor) treatment, which inevitably diminishes its therapeutic efficacy, provoking the need for higher doses associated with adverse effects. The proteolysis targeting chimera(PROTAC) technology has recently emerged as a powerful approach for inducing protein degradation. Nonetheless, due to their bifunctional nature, developing orally bioavailable PROTACs remains a great challenge. Herein, we identified a powerful HMGCR-targeted PROTAC(21 c) comprising a VHL ligand conjugated to lovastatin acid that potently degrades HMGCR in Insig-silenced HepG2 cells(DC50 Z 120 nmol/L) and forms a stable ternary complex, as predicated by a holistic modeling protocol. Most importantly, oral administration of the corresponding lactone 21 b reveled favorable plasma exposures referring to both the parent 21 b and the conversed acid 21 c. Further in vivo studies of 21 b demonstrated robust HMGCR degradation and potent cholesterol reduction in mice with diet-induced hypercholesterolemia, highlighting a promising strategy for treating hyperlipidemia and associated diseases.展开更多
胆固醇稳态对机体正常的生命活动至关重要,3-羟基-3-甲基戊二酸单酰辅酶A还原酶(3-hydroxy-3-methyl glutaryl coenzyme A reductase,HMGCR)介导的甲羟戊酸途径是机体胆固醇从头合成的关键步骤,因此,HMGCR的表达及调控对机体胆固醇稳态...胆固醇稳态对机体正常的生命活动至关重要,3-羟基-3-甲基戊二酸单酰辅酶A还原酶(3-hydroxy-3-methyl glutaryl coenzyme A reductase,HMGCR)介导的甲羟戊酸途径是机体胆固醇从头合成的关键步骤,因此,HMGCR的表达及调控对机体胆固醇稳态的维持十分重要。在机体内,HMGCR从转录到发挥其还原酶的功能这一过程受到了严格的调控,包括转录、翻译、蛋白稳定性及酶活性、表观遗传调控等方面。该文较全面地梳理和综述了该关键酶表达和调控的研究进展,为针对HMGCR调控胆固醇代谢的研究提供理论参考及思路。展开更多
基金supported by grants from Postdoctoral Research Foundation of China (2019M662007)National Natural Science Foundation of China (81874286)。
文摘HMG-CoA reductase(HMGCR) protein is usually upregulated after statin(HMGCR inhibitor) treatment, which inevitably diminishes its therapeutic efficacy, provoking the need for higher doses associated with adverse effects. The proteolysis targeting chimera(PROTAC) technology has recently emerged as a powerful approach for inducing protein degradation. Nonetheless, due to their bifunctional nature, developing orally bioavailable PROTACs remains a great challenge. Herein, we identified a powerful HMGCR-targeted PROTAC(21 c) comprising a VHL ligand conjugated to lovastatin acid that potently degrades HMGCR in Insig-silenced HepG2 cells(DC50 Z 120 nmol/L) and forms a stable ternary complex, as predicated by a holistic modeling protocol. Most importantly, oral administration of the corresponding lactone 21 b reveled favorable plasma exposures referring to both the parent 21 b and the conversed acid 21 c. Further in vivo studies of 21 b demonstrated robust HMGCR degradation and potent cholesterol reduction in mice with diet-induced hypercholesterolemia, highlighting a promising strategy for treating hyperlipidemia and associated diseases.
文摘胆固醇稳态对机体正常的生命活动至关重要,3-羟基-3-甲基戊二酸单酰辅酶A还原酶(3-hydroxy-3-methyl glutaryl coenzyme A reductase,HMGCR)介导的甲羟戊酸途径是机体胆固醇从头合成的关键步骤,因此,HMGCR的表达及调控对机体胆固醇稳态的维持十分重要。在机体内,HMGCR从转录到发挥其还原酶的功能这一过程受到了严格的调控,包括转录、翻译、蛋白稳定性及酶活性、表观遗传调控等方面。该文较全面地梳理和综述了该关键酶表达和调控的研究进展,为针对HMGCR调控胆固醇代谢的研究提供理论参考及思路。
