Abstract
Drug candidates derived from oligonucleotides (ON) are receiving increased attention that is supported by the clinical approval of several ON drugs. Such therapeutic ON are designed to alter the expression levels of specific disease-related proteins, e.g., by displaying antigene, antisense, and RNA interference mechanisms. However, the high polarity of the polyanionic ON and their relatively rapid nuclease-mediated cleavage represent two major pharmacokinetic hurdles for their application in vivo. This has led to a range of non-natural modifications of ON structures that are routinely applied in the design of therapeutic ON. The polyanionic architecture of ON often hampers their penetration of target cells or tissues, and ON usually show no inherent specificity for certain cell types. These limitations can be overcome by conjugation of ON with molecular entities mediating cellular ‘targeting’, i.e., enhanced accumulation at and/or penetration of a specific cell type. In this context, the use of small molecules as targeting units appears particularly attractive and promising. This review provides an overview of advances in the emerging field of cellular targeting of ON via their conjugation with small-molecule targeting structures.
Highlights
The results showed a clear downregulation of lamin A mRNA in a range of tissues, in mammary glands by 60% at 40 nmol per mouse after 48 h, whereas non-conjugated small interfering RNA (siRNA) did not exhibit effects in any tissue at all
The main strategy for inhibiting genes expressed in hepatocytes involves the exploitation of the asialoglycoprotein (Ashwell-Morell) receptor that is highly expressed in hepatocytes [286]
ApoB-100 plasma levels were found to be decreased by 68% after 24 h, and the total amount of cholesterol was shown to be reduced by 40% at a dose of 50 mg/kg
Summary
It leads to prolonged plasma half-lives [75] and reduced at the phosphate unit furnishes a novel stereogenic center at the phosphorus atom [72], resulting in diastereomers with either (SP ) or (RP ) configurations These show different properties in terms of nuclease stability and binding affinity to the complementary (target) strand [17,18]. An additional introduction of an N2 -imidazolylpropyl moiety in DAP strongly enhanced duplex stability without impeding RNase H activation at several positions within an ASO strand due to interactions with the phosphate backbone in the minor groove [133]. N2 -imidazolylpropyl [133] and N2 -aminopropyl derivatives of guanine [136] afforded strongly improved thermal stabilities and retained RNase H activation when placed in DNA or RNA, due to interactions with the phosphate backbone of the counterstrand
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