Chemistry of Peptide-Oligonucleotide Conjugates: A Review

Abstract

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.

Anticoagulant Oligonucleotide–Peptide Conjugates: Identification of Thrombin Aptamer Conjugates with Improved Characteristics

“…Due to the numerous functional roles that peptides and nucleic acids play in living organisms, OPCs have a wide range of potential applications. In particular, OPCs are a promising class of synthetic agents for nucleic acid therapeutics [ 1 , 2 , 3 , 4 ]. To a large extent, interest in OPCs is driven by the demand for tools to accomplish the efficient delivery of therapeutic nucleic acids to cells.…”

“…The suggested chemical tools to synthesize OPCs are either post-synthetic conjugation or stepwise solid-phase assembly of peptide–oligonucleotide sequences on a single solid support [ 4 , 15 , 16 ]. The former approach seems straightforward and easy to implement, since it is not complicated by compatibility issues between protocols for peptide and oligonucleotide syntheses, that are notably different.…”

Chemical optimization of siRNA for safe and efficient silencing of placental sFLT1

“…While the GalNac conjugate is the basis of currently approved siRNA drugs (i.e., givosiran), 69 , 70 it delivers to the liver only. 71 , 72 , 73 Several strategies are being explored to achieve extrahepatic delivery, including antibody conjugates, 74 , 75 peptide conjugates, 76 , 77 multivalency, 39 and hydrophobic conjugates. 30 DIO is widely distributed and retained in mouse brains compared to mono-siRNA, likely due to its increased size and cooperativity of PS-driven cellular uptake, 39 but multivalency did not support placental delivery ( Figure 2 ).…”

Precision Anti-Cancer Medicines by Oligonucleotide Therapeutics in Clinical Research Targeting Undruggable Proteins and Non-Coding RNAs

“…The phosphorothioate modification of the backbone greatly improved the binding of the oligonucleotides to the plasma proteins, increasing the time of the oligonucleotides in the circulation, while reducing their elimination. In vivo stability and resistance to degradation by DNases or RNases have been greatly improved by the different chemical modifications introduced in the nucleotides and in the backbone [ 130 , 131 ]. Regarding the delivery to the target cells, oligonucleotides are hydrophilic molecules and cannot passively cross the plasma membrane in the same way as the small molecule lipophilic drugs.…”