Lipid and Peptide-Oligonucleotide Conjugates for Therapeutic Purposes: From Simple Hybrids to Complex Multifunctional Assemblies

Abstract

Antisense and small interfering RNA (siRNA) oligonucleotides have been recognized as powerful therapeutic compounds for targeting mRNAs and inducing their degradation. However, a major obstacle is that unmodified oligonucleotides are not readily taken up into tissues and are susceptible to degradation by nucleases. For these reasons, the design and preparation of modified DNA/RNA derivatives with better stability and an ability to be produced at large scale with enhanced uptake properties is of vital importance to improve current limitations. In the present study, we review the conjugation of oligonucleotides with lipids and peptides in order to produce oligonucleotide conjugates for therapeutics aiming to develop novel compounds with favorable pharmacokinetics.

Targeting Peptides: The New Generation of Targeted Drug Delivery Systems

“…The N-terminus of an amino acid or the side-chain of a lysine or cysteine can be conjugated with fatty acids, such as caprylic acid (C8), capric acid (C10), lauric acid (C12), myristic acid (C14), palmitic acid (C16), or stearic acid (C18). Peptides' derivatization to lipids can be used for a number of different applications, e.g., (1) for improving peptide half-life in the circulation, mostly using long-chain fatty acids; (2) for increasing their antibacterial activity; (3) for raising the eukaryotic cell toxicity; and (4) for a faster passage through the cell membranes [99][100][101][102]. Moreover, derivatization of a peptide can also be performed with cholesterol via an N-or C-terminal inserted cysteine, especially in order to increase the potency of antiviral peptides, as an efficient gene delivery vector, for anticancer drug delivery, or when the peptide has a low in vivo half-life [103][104][105][106][107].…”

Drug-Grafted DNA for Cancer Therapy

“…In the design of pharmaceutically active compounds or chemical biology probes, peptides and oligonucleotides have typically been treated as separate biomolecules. In recent years, however, increasing interest has shifted toward conjugates as the combination of peptide and nucleic acid offers unique functionalities and may help overcome limitations like therapeutic transportation, delivery and localization in the targeted cellular structure. − From such points of view, peptide-grafted DNA has shown great promise as an alternative and advanced material for the technology of genetic medicines and novel functional nucleic acids.…”

Oligoribonucleotide-Containing Nanocomplexes Based on Aminopropylsilanol Nanoparticles as Effective Inhibitors of Influenza a Virus Replication

“…Основной проблемой является низкая биодоступность конъюгатов и неблагоприятная фармакокинетика, что вместе с довольно высокой стоимостью получения таких препаратов в количествах, необходимых для достижения терапевтического эффекта, затрудняет их использование в клинике [1]. Серьезный успех с применени-ем биоконъюгатов был достигнут в последнее время при использовании конъюгатов siRNA и N-aцетилгалактозамина (GalNAc), которые эффективно доставляются в гепатоциты путем связывания GalNAc с рецепторами печени [2]. В последние годы несколько препаратов siRNA были одобрены Управлением по санитарному надзору за качеством пищевых продуктов и медикаментов (США) или находятся на разных стадиях клинических испытаний [3].…”