Identification of a peptide inhibitor disrupting the PCSK9-LDLR interaction via pharmacophore-based virtual screening, molecular dynamics simulations and in vitro/vivo evaluation

Q: What is the clinical evidence from this study?

Population: Atherosclerotic cardiovascular disease (ASCVD). Intervention: TPP-4 vs. Pep2-8. Primary outcome: Binding affinity (Kd).

Wanling Wu; Shudan Yang; Jie Liu; Yuting Wang; Defeng Pan; Yafeng Zhou

doi:10.1080/14756366.2025.2610849

January 22, 2026Journal of Enzyme Inhibition and Medicinal ChemistryOpen Access

Identification of a peptide inhibitor disrupting the PCSK9-LDLR interaction via pharmacophore-based virtual screening, molecular dynamics simulations and in vitro/vivo evaluation

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Key result

Novel PCSK9 peptide inhibitor TPP-4 binds with ~0.08 μM affinity and lowers cholesterol in mice.

Why the study?

Does the TPP-4 peptide inhibitor disrupt the PCSK9-LDLR interaction and reduce plasma total cholesterol in preclinical models?

Key Points

The aim is to identify a peptide that disrupts the PCSK9-LDLR interaction to provide a new therapeutic option for ASCVD.
Conducted structure-based virtual screening to identify peptide inhibitors.
Compared identified peptide TPP-4 with control peptide Pep2-8.
Evaluated binding affinity and interactions using molecular dynamics simulations.
Assessed cytotoxicity in HepG2 cells and serum stability in vitro.
Evaluated lipid levels in mice after peptide treatment.
TPP-4 demonstrated a lower binding free energy of approximately -9.8 kcal/mol.
Measured Kd value of TPP-4 was 0.08 ± 0.01 μM, indicating high affinity.
In vitro, TPP-4 showed negligible cytotoxicity and restored LDLR function.
In vivo studies in mice revealed TPP-4 upregulated hepatic LDLR and reduced total cholesterol.

Structured PICO

Does the TPP-4 peptide inhibitor disrupt the PCSK9-LDLR interaction and reduce plasma total cholesterol in preclinical models?

P

Population

In vitro models (HepG2 cells, PCSK9 protein) and in vivo mouse models

I

Intervention

TPP-4 peptide inhibitor targeting PCSK9

C

Comparator

Pep2-8 (control peptide) for binding assays

O

Outcome

Binding affinity (Kd), binding free energy, surface LDLR restoration, and plasma total cholesterol levelssurrogate

Implication

TPP-4 is a novel, high-affinity peptide inhibitor of PCSK9 that restores LDLR and reduces total cholesterol in preclinical models, offering a potential candidate for ASCVD treatment.

Abstract

The PCSK9-LDLR interaction, driving elevated LDL-C, is a key driver of ASCVD pathogenesis. Identifying peptides disrupting this interaction offers an alternative ASCVD therapy. Herein, via structure-based virtual screening with Pep2-8 as a control, we identified TPP-4, a high-affinity peptide inhibitor targeting PCSK9. Compared to Pep2-8, TPP-4 showed lower binding free energy (approximately -9.8 kcal/mol) and Kd values (Kd = 0.08 ± 0.01 μM), interacting with PCSK9's LDLR-binding domain through multiple interactions. CD spectroscopy also provided indirect evidence for these key interactions. Additionally, it stably bound to the LDLR binding domain of PCSK9 during 100 ns MD simulations. It showed good serum stability, negligible HepG2 cytotoxicity, and restored surface LDLR (EC₅₀ = 1.12 ± 0.05 μM). In mice, TPP-4 upregulated hepatic LDLR and reduced plasma total cholesterol levels. In conclusion, these data demonstrate that TPP-4 could be a high-affinity and potent candidate peptide for ASCVD treatment.

Discussion

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Cite This Study

Wu et al. (2026) studied Atherosclerotic cardiovascular disease (ASCVD). TPP-4 vs. Pep2-8 was evaluated on Binding affinity (Kd). TPP-4, a high-affinity peptide inhibitor targeting PCSK9, demonstrated strong binding affinity (Kd = 0.08 μM), restored surface LDLR, and reduced plasma total cholesterol levels in mice.

synapsesocial.com/papers/69746126bb9d90c67120b0be https://doi.org/10.1080/14756366.2025.2610849

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Identification of a peptide inhibitor disrupting the PCSK9-LDLR interaction via pharmacophore-based virtual screening, molecular dynamics simulations and in vitro/vivo evaluation

Key Points

Structured PICO

Implication

Abstract

Discussion

Cite This Study

Identification of a peptide inhibitor disrupting the PCSK9-LDLR interaction via pharmacophore-based virtual screening, molecular dynamics simulations and in vitro/vivo evaluation

Key Points

Structured PICO

Implication

Abstract

Discussion

Cite This Study

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