2. Academic Validation
  3. CADD-engineered peptide protacs efficiently target PCSK9 for hypercholesterolemia in vivo

CADD-engineered peptide protacs efficiently target PCSK9 for hypercholesterolemia in vivo

  • Metabolism. 2025 Dec 23:176:156485. doi: 10.1016/j.metabol.2025.156485.
Gang Fan 1,  Weiming Guo 2,  Jingfen Lu 3,  Yaohui He 4,  Jinhui Zha 5,  Qingping Zhang 6,  Yuling Chen 7,  Dong Tan 5,  Zhihan Tang 8,  Jing Yang 9,  Zhijian Yu 10,  Miao Liu 11
Affiliations

Affiliations

  • 1 Medical Research Center, Affiliated Nanshan Hospital of Shenzhen University, Shenzhen, 518000, China; Pan-Vascular Research Group, Shenzhen University Affiliated Sixth Hospital, 518000, Shenzhen, Guangdong, China.
  • 2 Department of Orthopaedics, The First Affiliated Hospital of Guilin Medical University, Guilin, 541000, China; Pan-Vascular Research Group, Shenzhen University Affiliated Sixth Hospital, 518000, Shenzhen, Guangdong, China.
  • 3 The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
  • 4 Institute for Future Sciences, University of South China, Changsha, 410008, China.
  • 5 Medical Research Center, Affiliated Nanshan Hospital of Shenzhen University, Shenzhen, 518000, China.
  • 6 Department of Neurosurgery, Affiliated Nanshan Hospital of Shenzhen University, Shenzhen, 518052, China; Pan-Vascular Research Group, Shenzhen University Affiliated Sixth Hospital, 518000, Shenzhen, Guangdong, China.
  • 7 Department of Rheumatology and Immunology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.
  • 8 Institute of Cardiovascular Disease, , Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China; School of Basic Medical Sciences, Hunan University of Medicine, Huaihua, 418000, China. Electronic address: [email protected].
  • 9 Department of Endocrinology, Affiliated Nanshan Hospital of Shenzhen University, Shenzhen, 518052, China; Pan-Vascular Research Group, Shenzhen University Affiliated Sixth Hospital, 518000, Shenzhen, Guangdong, China. Electronic address: [email protected].
  • 10 Infectious Diseases Department, Affiliated Nanshan Hospital of Shenzhen University, Shenzhen, 518000, China. Electronic address: [email protected].
  • 11 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States. Electronic address: [email protected].
PMID: 41448485 DOI: 10.1016/j.metabol.2025.156485
Abstract

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.

Keywords

Hypercholesterolemia; In vivo; PCSK9; Plasma cholesterol; Targeted protein degradation.

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