A chimeric peptide of intestinal trefoil factor containing cholesteryl ester transfer protein B cell epitope significantly inhibits atherosclerosis in rabbits after oral administration

Qi, Gaofu; Li, Jingjing; Wang, Shengying; Xin, Shanshan; Zhang, Qingye; Zhao, Xiuyun

doi:10.1016/j.peptides.2010.12.014

Cited by 10 publications

(9 citation statements)

References 28 publications

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“…[23] We opted to design a trivalent vaccine candidate targeting the first approach; specifically, we designed vaccine candidates targeting apolipoprotein B (ApoB), CETP, and PCSK9. These target "cholesterol checkpoints" proteins are validated targets and safety and efficacy in animal models [12][13][14][15][16][17][18][19][20][21] or in humans [24][25][26] has been demonstrated using active and passive immunotherapy approaches.…”

Section: Introductionmentioning

confidence: 99%

A Single‐Dose, Implant‐Based, Trivalent Virus‐like Particle Vaccine against “Cholesterol Checkpoint” Proteins

Ortega-Rivera

Pokorski

Steinmetz

2021

Advanced Therapeutics

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Cardiovascular disease is the number one cause of death globally. Lowering cholesterol levels in plasma is the mainstay therapy; however lifelong treatment and adverse effects call for improved therapeutic interventions. A trivalent vaccine candidate targeting proprotein convertase subtilisin/kexin-9 (PCSK9), apolipoprotein B (ApoB), and cholesteryl ester transfer protein (CETP) is developed. Vaccine candidates are developed using bacteriophage Q -based virus-like particles (VLPs) displaying antigens of PCKS9, ApoB, and CETP, respectively. Vaccine candidate mixtures are formulated as slow-release PLGA:VLP implants using hot-melt extrusion. The delivery of the trivalent vaccine candidate via the implant produced antibodies against the cholesterol checkpoint proteins at levels comparable to a three-dose injection schedule with soluble mixtures. The reduction in PCSK9 and ApoB levels in plasma, inhibition of CETP (in vitro), and total plasma cholesterol decrease is achieved. Altogether, a platform technology for a single-dose multi-agent proteins is presented.

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Section: Introductionmentioning

confidence: 99%

A Single‐Dose, Implant‐Based, Trivalent Virus‐like Particle Vaccine against “Cholesterol Checkpoint” Proteins

Ortega-Rivera

Pokorski

Steinmetz

2021

Advanced Therapeutics

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“… 28 It was thus important to characterize TFF3’s gastrointestinal stability in more detail, particularly considering that studies often rely on the use of sodium dodecyl sulfate (SDS) gels and antibodies to identify and characterize TFF3, where truncations can easily be missed. 48 , 49 , 66 …”

Section: Resultsmentioning

confidence: 99%

Chemical Synthesis of TFF3 Reveals Novel Mechanistic Insights and a Gut-Stable Metabolite

et al. 2021

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TFF3 regulates essential gastro- and neuroprotective functions, but its molecular mode of action remains poorly understood. Synthetic intractability and lack of reliable bioassays and validated receptors are bottlenecks for mechanistic and structure–activity relationship studies. Here, we report the chemical synthesis of TFF3 and its homodimer via native chemical ligation followed by oxidative folding. Correct folding was confirmed by NMR and circular dichroism, and TFF3 and its homodimer were not cytotoxic or hemolytic. TFF3, its homodimer, and the trefoil domain (TFF3 10-50 ) were susceptible to gastrointestinal degradation, revealing a gut-stable metabolite (TFF3 7-54 ; t 1/2 > 24 h) that retained its trefoil structure and antiapoptotic bioactivity. We tried to validate the putative TFF3 receptors CXCR4 and LINGO2, but neither TFF3 nor its homodimer displayed any activity up to 10 μM. The discovery of a gut-stable bioactive metabolite and reliable synthetic accessibility to TFF3 and its analogues are cornerstones for future molecular probe development and structure–activity relationship studies.

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“…Intramuscular DNA vaccination targeting CETP has been shown to be similarly effective as a peptide-based vaccination [26]. A new factor was introduced whereby human intestinal trefoil factor (TFF3) was employed as a molecular vehicle for the CETP B-cell epitope, which allows oral administration of the chimeric peptide [27].…”

Section: Lipid-based Vaccination Strategiesmentioning

confidence: 99%

New Alternatives for Atherosclerosis Treatment Based on Immunomodulation

Roche

Hernández

2012

ISRN Vascular Medicine

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Atherosclerosis and its derived cardiovascular diseases are a leading cause of death in the western world. The treatment of atherosclerosis is currently based on lipid lowering in combination with anti-inflammatory therapies that slow the progression of atherosclerosis. Still, these therapies are not able to fully inhibit the formation or progression of atherosclerotic lesions. Ever since it was first demonstrated that the immunological system plays an important role during atherogenesis, various different immunotherapeutic approaches have been evaluated with promising results. Notwithstanding that, one of the difficulties in developing effective vaccination strategies for atherosclerosis is the selection of a specific target. So far, vaccination strategies have been based on the targeting of lipid antigens, inflammation-derived antigens, and cell-based vaccination strategies. More recently, strategies aimed at blocking the retention of low-density lipoproteins by arterial proteoglycans have emerged as a promising tool. In the study at hand we reviewed the most relevant advances on atherosclerosis immunotherapy cited in the PubMed database from 1980 to 2012.

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A chimeric peptide of intestinal trefoil factor containing cholesteryl ester transfer protein B cell epitope significantly inhibits atherosclerosis in rabbits after oral administration

Cited by 10 publications

References 28 publications

A Single‐Dose, Implant‐Based, Trivalent Virus‐like Particle Vaccine against “Cholesterol Checkpoint” Proteins

A Single‐Dose, Implant‐Based, Trivalent Virus‐like Particle Vaccine against “Cholesterol Checkpoint” Proteins

Chemical Synthesis of TFF3 Reveals Novel Mechanistic Insights and a Gut-Stable Metabolite

New Alternatives for Atherosclerosis Treatment Based on Immunomodulation

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