Journal
MOLECULES
Volume 26, Issue 17, Pages -Publisher
MDPI
DOI: 10.3390/molecules26175420
Keywords
cell-penetrating peptide; nucleic acid therapeutic; antisense oligonucleotide; small interfering RNA (siRNA); peptide nucleic acid (PNA); locked nucleic acid (LNA); phosphordiamidate morpholino oligomer (PMO); cellular uptake; drug delivery; click chemistry
Funding
- Russian Foundation for Basic Research [18-515-57006, 18-29-08062, 18-29-09045]
- Ministry of Science and Higher Education of the Russian Federation (project of Novosibirsk State University) [FSUS-2020-0035]
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This article discusses the importance of peptide-oligonucleotide conjugates in enhancing the efficiency of therapeutic nucleic acids and the related chemical synthesis methods, which are mainly divided into two strategies: stepwise solid-phase synthesis and post-synthetic conjugation.
Peptide-oligonucleotide conjugates (POCs) represent one of the increasingly successful albeit costly approaches to increasing the cellular uptake, tissue delivery, bioavailability, and, thus, overall efficiency of therapeutic nucleic acids, such as, antisense oligonucleotides and small interfering RNAs. This review puts the subject of chemical synthesis of POCs into the wider context of therapeutic oligonucleotides and the problem of nucleic acid drug delivery, cell-penetrating peptide structural types, the mechanisms of their intracellular transport, and the ways of application, which include the formation of non-covalent complexes with oligonucleotides (peptide additives) or covalent conjugation. The main strategies for the synthesis of POCs are viewed in detail, which are conceptually divided into (a) the stepwise solid-phase synthesis approach and (b) post-synthetic conjugation either in solution or on the solid phase, especially by means of various click chemistries. The relative advantages and disadvantages of both strategies are discussed and compared.
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