The Use of Therapeutic Peptides to Target and to Kill Cancer Cells

Boohaker, Rebecca J.; Lee, M. W.; Vishnubhotla, Priya; Perez, J.L. M.; Khaled, Annette R.

doi:10.2174/092986712801661004

Cited by 293 publications

(226 citation statements)

References 115 publications

Supporting

Mentioning

219

Contrasting

Unclassified

Order By: Relevance

“…In particular, amphiphilic peptides, especially those amphiphilic peptides containing long cationic tails, selectively bind to cancer cells and cause cell death by cytoplasmic membrane disruption, whereas others trigger apoptosis via death receptor or mitochondrial pathways (52,53). It should be noted, however, that a version of ReAcp53 with a shuffled sequence is not cytotoxic (40).…”

Section: Peptides and Peptide Combinations Selectively Kill Cancer Cementioning

confidence: 99%

Multisite aggregation of p53 and implications for drug rescue

Wang

Fersht

2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Protein aggregation is involved in many diseases. Often, a unique aggregation-prone sequence polymerizes to form regular fibrils. Many oncogenic mutants of the tumor suppressor p53 rapidly aggregate but form amorphous fibrils. A peptide surrounding Ile254 is proposed to be the aggregation-driving sequence in cells. We identified several different aggregating sites from limited proteolysis of harvested aggregates and effects of mutations on kinetics and products of aggregation. We present a model whereby the amorphous nature of the aggregates results from multisite branching of polymerization after slow unfolding of the protein, which may be a common feature of aggregation of large proteins. Greatly lowering the aggregation propensity of any one single site, including the site of Ile254, by mutation did not inhibit aggregation in vitro because aggregation could still occur via the other sites. Inhibition of an individual site is, accordingly, potentially unable to prevent aggregation in vivo. However, cancer cells are specifically killed by peptides designed to inhibit the Ile254 sequence and further aggregation-driving sequences that we have found. Consistent with our proposed mechanism of aggregation, we found that such peptides did not inhibit aggregation of mutant p53 in vitro. The cytotoxicity was not eliminated by knockdown of p53 in 2D cancer cell cultures. The peptides caused rapid cell death, much faster than usually expected for p53-mediated transcription-dependent apoptosis. There may also be non-p53 targets for those peptides in cancer cells, such as p63, or the peptides may alter other interactions of partly denatured p53 with receptors.amyloid | mechanism | misfolding | disease T he tumor suppressor p53 is inactivated by mutation in a substantial number of tumors (1-3). Some 30-40% of those oncogenic mutants are simply destabilized by mutations in its core domain. Those mutants are temperature-sensitive, having a WT structure at lower temperatures, but melt at close to body temperature or below and rapidly aggregate (4-6). Protein aggregation occurs in many diseases (7-9). The best mechanistically characterized examples involve the polymerization of aggregationprone peptides (10, 11) or small proteins to give well-defined fibrils based on a regular repeat structure (12-18). The fibrillar aggregates have a characteristic cross-β X-ray diffraction pattern and bind such dyes as Congo Red and Thioflavine T (ThT) (16). The kinetics of aggregation usually follow a nucleation-growth mechanism, with very slow nucleation (19-21). WT p53 itself aggregates at body temperature (4-6, 22-24), and the oncogenic destabilized mutants aggregate even faster to give amorphous structures that display the characteristic diffraction pattern and bind those diagnostic dyes (23, 25), although under certain conditions, such as very high pressure, they will generate regular fibrils (23,26). The mechanism of initiation of aggregation of p53 differs from the usually studied examples. Two molecules of the core domain of p53 exten...

show abstract

Section: Peptides and Peptide Combinations Selectively Kill Cancer Cementioning

confidence: 99%

Multisite aggregation of p53 and implications for drug rescue

Wang

Fersht

2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Indeed, peptide therapeutics is a promising field for emerging anti-cancer agents [12,30]. Benefits include the ease and rapid synthesis of peptides and capacity for modifications.…”

Section: Fundamental Applications Of Fluorocarbons In Oncologymentioning

confidence: 99%

“…apoptotic or necrotic cell death through disruption of cell or organelles membranes). For instance, amphiphilic peptides with clusters of hydrophobic and cationic residues showed considerable anticancer toxicity [30]. The main challenge still lies on improving delivery to tumors, minimizing non-specific toxic effects and discerning pharmacokinetic properties in order to produce a powerful therapeutic peptide for cancer treatment.…”

Section: Fundamental Applications Of Fluorocarbons In Oncologymentioning

confidence: 99%

Importance of Fluorine and Fluorocarbons in Medicinal Chemistry and Oncology

Menaa¹

2013

J Mol Pharm Org Process Res

View full text Add to dashboard Cite

“…6 In recent years, a number of peptide-based therapies have been tested in both in vitro and in vivo experimental models and applied to treat various types of cancer. 7 During the process of developing peptidebased drugs, many proteins have been selected as potential drug targets due to their critical roles in the pathogenesis of cancers. Of the various protein targets chosen, c-Src is an extensively studied kinase oncogene in academia and industry.…”

Section: Introductionmentioning

confidence: 99%

Optimizing the Amino Acid Sequences of Peptides and Improving Their Specificity of Binding to SH3 Domains of Target Proteins

Ren¹,

Wang²,

Li³

2017

IJPER

View full text Add to dashboard Cite

Introduction: It is always a crucial challenge in biotechnology to avoid promiscuous binding between an anticancer peptide and multiple SH3 domains, thus reducing potential toxic effects. In spite of a great deal of experimental efforts, the association between amino acid sequence and binding specificity of peptide remained largely unknown. Aim: The purpose of this study was to optimize the amino acid sequence of peptide ligands and render high specificity towards designated therapeutic targets. Results: By exploring peptide ligands in MINT database and utilizing SH3PepInt tool for in silico peptide-target binding, here we investigated how the amino acid sequence of a peptide determined its specificity of binding to the SH3 domain of c-Src protein. We found that the 5

show abstract

The Use of Therapeutic Peptides to Target and to Kill Cancer Cells

Cited by 293 publications

References 115 publications

Multisite aggregation of p53 and implications for drug rescue

Multisite aggregation of p53 and implications for drug rescue

Importance of Fluorine and Fluorocarbons in Medicinal Chemistry and Oncology

Optimizing the Amino Acid Sequences of Peptides and Improving Their Specificity of Binding to SH3 Domains of Target Proteins

Contact Info

Product

Resources

About