Abstract
The smooth identification and low-cost production of highly specific agents that interfere with signaling cascades by targeting an active domain in surface receptors, cytoplasmic and nuclear effector proteins, remain important challenges in biomedical research. We propose that peptide aptamers can provide a very useful and new alternative for interfering with protein–protein interactions in intracellular signal transduction cascades, including those emanating from activated receptors for growth factors. By their targeting of short, linear motif type of interactions, peptide aptamers have joined nucleic acid aptamers for use in signaling studies because of their ease of production, their stability, their high specificity and affinity for individual target proteins, and their use in high-throughput screening protocols. Furthermore, they are entering clinical trials for treatment of several complex, pathological conditions. Here, we present a brief survey of the use of aptamers in signaling pathways, in particular of polypeptide growth factors, starting with the published as well as potential applications of aptamers targeting Epidermal Growth Factor Receptor signaling. We then discuss the opportunities for using aptamers in other complex pathways, including Wnt/β-catenin, and focus on Transforming Growth Factor-β/Smad family signaling.
Highlights
The smooth identification and low-cost production of highly specific agents that interfere with signaling cascades by targeting an active domain in surface receptors, cytoplasmic and nuclear effector proteins, remain important challenges in biomedical research
We suggest that peptide aptamers will be ideal new tools to selectively inhibit a specific Smad activity based on their interaction with many Smad-interacting proteins (SIPs), rather than hitting by receptor-targeting drugs the entire Smad signaling pathway
Many nucleic acid aptamers and peptide aptamers, directed against various types of targets, initially often including proteins involved in EGF receptor (EGFR) signaling, have been selected, produced and validated
Summary
In 1990, Ellington and Szostak [1], in the context of their studies on self-splicing group I introns and ribozymes, reported on the production and characterization of short, random RNA sequences able to bind to one of various organic dyes used as target. Nucleic acid aptamers are short, single-stranded RNAs and DNAs that represent high-affinity and highly selective ligands for different targets, ranging from large proteins to peptides, nucleotides, drugs and small compounds, and even metal ions. Such aptamers can be isolated from combinatorial libraries by SELEX (systematic evolution of ligands by exponential enrichment) [3]. Perhaps the most popular scaffold protein for displaying constrained peptides is Thioredoxin-A (TrxA) of E. coli (Table 2) It has been chosen because of its small size (about 12 kDa), high stability and solubility, and its known secondary and tertiary structure [16,18,19]. Stefin A has been engineered to provide surface immobilization of the peptides as well as ensuring exposure of the binding site to the target solution, and avoiding any interactions with human proteins [23,24]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.