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Purpose <p>Small interfering RNA (siRNA) holds significant therapeutic promise, particularly for the treatment of central nervous system (CNS) disorders. However, its clinical translation remains limited by poor membrane permeability, inefficient cellular uptake, and the lack of effective targeted delivery strategies. This study aimed to develop a multifunctional peptide-based platform capable of enhancing siRNA delivery, including applications in nose-to-brain transport.</p> Methods <p>A lectin-mimicking cyclic peptide, odorranalectin (OL), was functionalized with positively charged cell-penetrating peptide (CPP) sequences. The cationic sequences were strategically incorporated at the N-terminus to preserve the carbohydrate-binding function of OL while enabling electrostatic complexation with RNA. RNA binding was evaluated using electrophoretic mobility shift assays (EMSA), while circular dichroism spectroscopy was employed to assess thermal stability of peptide/RNA complexes. Carbohydrate recognition was examined by isothermal titration calorimetry (ITC) using OL-TAT and asialofetuin as a model ligand system.</p> Results <p>Peptides containing higher numbers of cationic residues exhibited enhanced RNA-binding affinity and formed more stable peptide/RNA complexes. Importantly, incorporation of CPP sequences did not compromise the intrinsic carbohydrate-binding properties of odorranalectin.</p> Conclusion <p>The reported OL-based bifunctional peptides retain carbohydrate-recognition capabilities while enabling tunable and efficient RNA binding, demonstrating the successful integration of both functionalities within a single scaffold. These results highlight the potential of this platform for targeted siRNA delivery and support its further development as a strategy to overcome current limitations in brain-targeted RNA therapeutics.</p>

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Design and Synthesis of Odorranalectin-Derived Peptides for RNA Binding

  • 期刊论文

  • 发表日期：

    2026年6月18日

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  • Tamara Damjanovic,
  • Predrag Cudic

摘要

Purpose

Small interfering RNA (siRNA) holds significant therapeutic promise, particularly for the treatment of central nervous system (CNS) disorders. However, its clinical translation remains limited by poor membrane permeability, inefficient cellular uptake, and the lack of effective targeted delivery strategies. This study aimed to develop a multifunctional peptide-based platform capable of enhancing siRNA delivery, including applications in nose-to-brain transport.

Methods

A lectin-mimicking cyclic peptide, odorranalectin (OL), was functionalized with positively charged cell-penetrating peptide (CPP) sequences. The cationic sequences were strategically incorporated at the N-terminus to preserve the carbohydrate-binding function of OL while enabling electrostatic complexation with RNA. RNA binding was evaluated using electrophoretic mobility shift assays (EMSA), while circular dichroism spectroscopy was employed to assess thermal stability of peptide/RNA complexes. Carbohydrate recognition was examined by isothermal titration calorimetry (ITC) using OL-TAT and asialofetuin as a model ligand system.

Results

Peptides containing higher numbers of cationic residues exhibited enhanced RNA-binding affinity and formed more stable peptide/RNA complexes. Importantly, incorporation of CPP sequences did not compromise the intrinsic carbohydrate-binding properties of odorranalectin.

Conclusion

The reported OL-based bifunctional peptides retain carbohydrate-recognition capabilities while enabling tunable and efficient RNA binding, demonstrating the successful integration of both functionalities within a single scaffold. These results highlight the potential of this platform for targeted siRNA delivery and support its further development as a strategy to overcome current limitations in brain-targeted RNA therapeutics.