Metabolism: clinical and experimental · 2025
CADD-engineered peptide protacs efficiently target PCSK9 for hypercholesterolemia in vivo.
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Fan Gang, Guo Weiming, Lu Jingfen, He Yaohui, Zha Jinhui, Zhang Qingping, Chen Yuling, Tan Dong, Tang Zhihan, Yang Jing, Yu Zhijian, Liu Miao
Аннотация
BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of low-density lipoprotein receptors (LDLR), leading to elevated plasma LDL cholesterol (LDL-C) and increased risk of hypercholesterolemia. Current therapeutic approaches, such as monoclonal antibodies and gene-editing tools, face significant challenges including high cost, safety issues, and limited ability to target intracellular PCSK9.
METHODS: Using computer-aided drug design (CADD), we developed Cadd4, a novel peptide-based degrader targeting PCSK9. Molecular docking was employed to identify a high-affinity peptide sequence, which was then validated through in vitro studies using LX-2 cells and in vivo experiments in high-fat diet (HFD)-induced hypercholesterolemic mice. Biodistribution and toxicity assessments were performed to evaluate tissue specificity and safety. Human liver tissue experiments were conducted to assess translational efficacy.
RESULTS: Cadd4 exhibited efficient intracellular uptake and significantly reduced PCSK9 levels, resulting in upregulated LDLR expression. In HFD-fed mice, hepatic PCSK9 was decreased by 38 %, accompanied by a 25 % reduction in total cholesterol and a 29 % reduction in LDL-C. Biodistribution analysis revealed liver-specific accumulation with no signs of systemic toxicity. In human liver tissues, Cadd4 effectively degraded PCSK9 and restored LDLR expression. Compared with the clinical-stage PCSK9 inhibitor, Cadd4 demonstrated promising lipid-lowering efficacy and the potential for a longer duration of action.
CONCLUSION: Cadd4 represents a promising CADD-designed therapeutic strategy for cholesterol management by targeting intracellular PCSK9 for degradation. This approach overcomes key limitations of existing therapies and underscores the potential of targeted protein degradation in cardiovascular disease treatment.
METHODS: Using computer-aided drug design (CADD), we developed Cadd4, a novel peptide-based degrader targeting PCSK9. Molecular docking was employed to identify a high-affinity peptide sequence, which was then validated through in vitro studies using LX-2 cells and in vivo experiments in high-fat diet (HFD)-induced hypercholesterolemic mice. Biodistribution and toxicity assessments were performed to evaluate tissue specificity and safety. Human liver tissue experiments were conducted to assess translational efficacy.
RESULTS: Cadd4 exhibited efficient intracellular uptake and significantly reduced PCSK9 levels, resulting in upregulated LDLR expression. In HFD-fed mice, hepatic PCSK9 was decreased by 38 %, accompanied by a 25 % reduction in total cholesterol and a 29 % reduction in LDL-C. Biodistribution analysis revealed liver-specific accumulation with no signs of systemic toxicity. In human liver tissues, Cadd4 effectively degraded PCSK9 and restored LDLR expression. Compared with the clinical-stage PCSK9 inhibitor, Cadd4 demonstrated promising lipid-lowering efficacy and the potential for a longer duration of action.
CONCLUSION: Cadd4 represents a promising CADD-designed therapeutic strategy for cholesterol management by targeting intracellular PCSK9 for degradation. This approach overcomes key limitations of existing therapies and underscores the potential of targeted protein degradation in cardiovascular disease treatment.