Peptide–Oligonucleotide Conjugation: Chemistry and Therapeutic Applications

Abstract

Oligonucleotides have been identified as powerful therapeutics for treating genetic disorders and diseases related to epigenetic factors such as metabolic and immunological dysfunctions. However, they face certain obstacles in terms of limited delivery to tissues and poor cellular uptake due to their large size and often highly charged nature. Peptide–oligonucleotide conjugation is an extensively utilized approach for addressing the challenges associated with oligonucleotide-based therapeutics by improving their delivery, cellular uptake and bioavailability, consequently enhancing their overall therapeutic efficiency. In this review, we present an overview of the conjugation of oligonucleotides to peptides, covering the different strategies associated with the synthesis of peptide–oligonucleotide conjugates (POC), the commonly used peptides employed to generate POCs, with the aim to develop oligonucleotides with favourable pharmacokinetic (PK) or pharmacodynamic (PD) properties for therapeutic applications. The advantages and drawbacks of the synthetic methods and applications of POCs are also described.

Keywords

• peptide–oligonucleotide conjugates
• conjugation chemistry
• receptor-mediated oligonucleotide delivery
• nucleic acid therapeutics
• cellular uptake
• cell-penetrating peptides