Bioactive cell penetrating peptides and proteins in cancer: a bright future ahead

Jauset, Toni; Beaulieu, Marie-Ève

doi:10.1016/j.coph.2019.03.014

Cited by 40 publications

(33 citation statements)

References 80 publications

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“…Structural changes, such as folding and electron bonding, during protein expression appear to have resulted in the loss of the peptide's ability to control inflammation and bacteremia. There may also be functional differences between peptides and proteins (Jauset & Beaulieu, 2019). Nevertheless, its therapeutic effect in sepsis is due to the efficacy of the Rv2626c peptide ( 123 LPEHAIVQF 131 ), instead of the antibacterial activity of tuftsin; nevertheless, the potential effect of tuftsin on adaptive immunity remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosis Rv2626c‐derived peptide as a therapeutic agent for sepsis

Kim

et al. 2020

EMBO Mol Med

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The Rv2626c protein of Mycobacterium tuberculosis is a promising vaccine candidate owing to its strong serum antibody response in patients with tuberculosis. However, there is limited information regarding the intracellular response induced by Rv2626c in macrophages. In this study, we demonstrated that Rv2626c interacts with the RING domain of TRAF6 and inhibits lysine (K) 63-linked polyubiquitination of TRAF6 (E3 ubiquitin ligase activity); this results in the suppression of TLR4 inflammatory signaling in macrophages. Furthermore, we showed that the C-terminal 123-131-amino acid Rv2626c motif promotes macrophage recruitment, phagocytosis, M2 macrophage polarization, and subsequent bacterial clearance. We developed rRv2626c-CA, a conjugated peptide containing the Cterminal 123-131-amino acid Rv2626c that targets macrophages, penetrates the cell membrane, and has demonstrated significant therapeutic effects in a mouse model of cecal ligation and puncture-induced sepsis. This multifunctional rRv2626c-CA has considerably improved potency, with an IC 50 that is 250-fold (in vitro) or 1,000-fold (in vivo) lower than that of rRv2626c-WT. We provide evidence for new peptide-based drugs with anti-inflammatory and antibacterial properties for the treatment of sepsis.

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Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosis Rv2626c‐derived peptide as a therapeutic agent for sepsis

Kim

et al. 2020

EMBO Mol Med

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“…The data are representative of two independent experiments with similar results. fast metabolism, subunit dissociation, conformational changes, systemic proteolytic enzymes, opsonization, non-covalent complex formation with blood products, and modification of labile and reactive side-groups [18,28].…”

Section: Discussionmentioning

confidence: 99%

Toxoplasma gondii GRA8-derived peptide immunotherapy improves tumor targeting of colorectal cancer

et al. 2020

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Targeted tumor and efficient, specific biological drug delivery in vivo has been one of the main challenges in protein-based cancer-targeted therapies. Mitochondria are potential therapeutic targets for various anti-cancer drugs. We have previously reported that protein kinase Cα-mediated phosphorylation of Toxoplasma gondii GRA8 is required for mitochondrial trafficking and regulating the interaction of the C-terminal of GRA8 with ATP5A1/SIRT3 in mitochondria. Furthermore, SIRT3 facilitates ATP5A1 deacetylation, mitochondrial activation, and subsequent antiseptic activity in vivo. Herein we developed a recombinant acidity-triggered rational membrane (ATRAM)-conjugated multifunctional GRA8 peptide (rATRAM-G8-M/AS) comprising ATRAM as the cancer-targeting cell-penetrating peptide, and essential/ minimal residues for mitochondrial targeting or ATP5A1/SIRT3 binding. This peptide construct showed considerably improved potency about cancer cell death via mitochondria activity and biogenesis compared with rGRA8 alone in HCT116 human carcinoma cells, reaching an IC 50 value of up to 200-fold lower in vitro and 500-fold lower in vivo. Notably, rATRAM-G8-M/AS treatment showed significant therapeutic effects in a mouse xenograft model through mitochondrial metabolic resuscitation, and it produced negligible immunogenicity and immune responses in vivo. Thus, these results demonstrate that rATRAM-G8-M/AS represents a useful therapeutic strategy against tumors, particularly colon cancer. This strategy represents an urgently needed paradigm shift for therapeutic intervention.

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“…It can be used in high-dose and frequent intervals with the purpose of increasing exposure to reduce the immunogenicity of therapeutics, but this way results in toxicity. The other way is to inject therapeutics subcutaneously which can reduce the production of anti-drug antibodies caused by the immune system (Jauset and Beaulieu, 2019). (3) Cellular toxicity.…”

Section: Limitations Of Cpp-mediated Applicationmentioning

confidence: 99%

Cell-Penetrating Peptides in Diagnosis and Treatment of Human Diseases: From Preclinical Research to Clinical Application

et al. 2020

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Cell-penetrating peptides (CPPs) are short peptides (fewer than 30 amino acids) that have been predominantly used in basic and preclinical research during the last 30 years. Since they are not only capable of translocating themselves into cells but also facilitate drug or CPP/cargo complexes to translocate across the plasma membrane, they have potential applications in the disease diagnosis and therapy, including cancer, inflammation, central nervous system disorders, otologic and ocular disorders, and diabetes. However, no CPPs or CPP/cargo complexes have been approved by the US Food and Drug Administration (FDA). Many issues should be addressed before translating CPPs into clinics. In this review, we summarize recent developments and innovations in preclinical studies and clinical trials based on using CPP for improved delivery, which have revealed that CPPs or CPP-based delivery systems present outstanding diagnostic therapeutic delivery potential.

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Bioactive cell penetrating peptides and proteins in cancer: a bright future ahead

Cited by 40 publications

References 80 publications

Mycobacterium tuberculosis Rv2626c‐derived peptide as a therapeutic agent for sepsis

Mycobacterium tuberculosis Rv2626c‐derived peptide as a therapeutic agent for sepsis

Toxoplasma gondii GRA8-derived peptide immunotherapy improves tumor targeting of colorectal cancer

Cell-Penetrating Peptides in Diagnosis and Treatment of Human Diseases: From Preclinical Research to Clinical Application

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