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.
Highlights
The peptide-oligonucleotide conjugate (POC) is a name usually applied to a synthetic molecule constituting one or more residues of a linear or, less often, a cyclic peptide linked by a covalent bond to an oligonucleotide or its analog
The compounds related to POCs occur in nature as nucleopeptides [1,2,3], this review, as it is focused on the chemical methods of conjugating peptides to oligonucleotides, will be necessarily limited to synthetic substances only
The undoubted advantage of the stepwise solid-phase synthesis approach is the absence of time-consuming isolation and purification of the individual peptide and oligonucleotide fragments of the conjugate
Summary
The peptide-oligonucleotide conjugate (POC) is a name usually applied to a synthetic molecule constituting one or more residues of a linear or, less often, a cyclic peptide linked by a covalent bond to an oligonucleotide or its analog. After a period of research, it was generally accepted that a successful nucleic acid drug ought to demonstrate better cellular uptake than what the majority of the explored to-date oligonucleotide chemistries can offer [7,8] This understanding coincided with the serendipitous discovery of what was later to be called cell-penetrating peptides in the mid-1990s [9]. The progress in non-clinical and clinical studies with synthetic oligonucleotides has prompted the FDA approval of a total of 12 drugs, whereas over 130 are going through various phases of clinical trials [14,15] Despite their huge therapeutic potential, oligonucleotides and their analogs, due to their intrinsic physicochemical characteristics, in most cases face the problem of ineffective transport through the cellular membrane, usually via an endocytotic pathway [16,17]. An overview of the currently applicable methods for the chemical synthesis of peptide-oligonucleotide conjugates, with particular emphasis on more recent developments, would be useful for an in-depth understanding of this highly promising area of oligonucleotide therapeutics research
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