TY - JOUR

T1 - Chemistry of peptide-oligonucleotide conjugates: A review

AU - Klabenkova, Kristina

AU - Fokina, Alesya

AU - Stetsenko, Dmitry

N1 - Funding Information: This work was funded by the Russian Foundation for Basic Research (grant nos. 18-515-57006, 18-29-08062, and 18-29-09045) and the Ministry of Science and Higher Education of the Russian Federation (project of Novosibirsk State University, no. FSUS-2020-0035). Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2021/9

Y1 - 2021/9

N2 - 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.

AB - 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.

KW - Antisense oligonucleotide

KW - Cell-penetrating peptide

KW - Cellular uptake

KW - Click chemistry

KW - Drug delivery

KW - Locked nucleic acid (LNA)

KW - Nucleic acid therapeutic

KW - Peptide nucleic acid (PNA)

KW - Phosphordiamidate morpholino oligomer (PMO)

KW - Small interfering RNA (siRNA)

UR - http://www.scopus.com/inward/record.url?scp=85114616830&partnerID=8YFLogxK

U2 - 10.3390/molecules26175420

DO - 10.3390/molecules26175420

M3 - Review article

C2 - 34500849

AN - SCOPUS:85114616830

VL - 26

JO - Molecules

JF - Molecules

SN - 1420-3049

IS - 17

M1 - 5420

ER -