Pinpointed Stimulation of EphA2 Receptors via DNA-Templated Oligovalence

Abstract

DNA nanostructures enable the attachment of functional molecules to nearly any unique location on their underlying structure. Due to their single-base-pair structural resolution, several ligands can be spatially arranged and closely controlled according to the geometry of their desired target, resulting in optimized binding and/or signaling interactions. Here, the efficacy of SWL, an ephrin-mimicking peptide that binds specifically to EphrinA2 (EphA2) receptors, increased by presenting up to three of these peptides on small DNA nanostructures in an oligovalent manner. Ephrin signaling pathways play crucial roles in tumor development and progression. Moreover, Eph receptors are potential targets in cancer diagnosis and treatment. Here, the quantitative impact of SWL valency on binding, phosphorylation (key player for activation) and phenotype regulation in EphA2-expressing prostate cancer cells was demonstrated. EphA2 phosphorylation was significantly increased by DNA trimers carrying three SWL peptides compared to monovalent SWL. In comparison to one of EphA2’s natural ligands ephrin-A1, which is known to bind promiscuously to multiple receptors, pinpointed targeting of EphA2 by oligovalent DNA-SWL constructs showed enhanced cell retraction. Overall, we show that DNA scaffolds can increase the potency of weak signaling peptides through oligovalent presentation and serve as potential tools for examination of complex signaling pathways.

Challenges and Perspectives of DNA Nanostructures in Biomedicine

“…Möser et al. recently conjugated ephrin‐mimicking peptides that bind to EphrinA2 receptors to the tips of a DNA three‐arm junction . Ephrin‐signaling pathways are involved in tumor development and may thus be utilized in cancer therapy.…”

DNA Nanostructures in the Fight Against Infectious Diseases

“…The modularity of these systems is of key importance, as small, synthetic antigens for a variety of different viruses or pathogens can be easily interchanged at will. Conjugation techniques for attaching peptides to different types of DNA nanostructures are now well‐established [ 88,139 ] and can be directly transferred to synthetically produced polysaccharide antigens or glycopeptide chimera of the two. As high‐quality structural studies combined with in silico modeling can even provide candidate antigenic sequences of new threats within a few months of their emergence, [ 140 ] the establishment of pipelines effective for rational design and molecular construction of vaccines against viral threats could eventually become part of a rapid response against new threats.…”

“…This allows active, therapeutic molecules to be combined with additional targeting or stimulatory moieties in a manner rationally designed to enhance the overall efficacy. Indeed, several preliminary studies on both cellular [85][86][87][88] and animal models [86,89,90] have pointed toward the future promise of this approach. Nevertheless, relatively few studies have focused on battling pathogenic infections; rather, cancer has been the most popular target for DNA-based particles to deliver chemotherapeutic molecules [86,87,90,91] or train the immune system to attack tumors.…”

Smart Nanocarriers for the Delivery of Nucleic Acid‐Based Therapeutics: A Comprehensive Review

“…The delivery of Ephrin‐mimicking peptides successfully increased the phosphorylation of EphA2 in prostate cancer cells and suppressed tumor proliferation. [ 127 ] Besides small molecules, DN could be utilized to deliver several nucleic acids, including siRNA, miRNA, and complementary genes. [ 128,129 ] For example, Lee et al.…”