Chemical Modifications in Nucleic Acids for Therapeutic and Diagnostic Applications

Abstract

The last decade has witnessed the blooming of nucleic acids for therapeutic and diagnostic applications. In the present article, we describe the most important results from our group in this area covering the international context that surrounded this research. These include the study of modifications at the terminal and internal positions of siRNA duplexes to enhance nuclease resistance, increase loading of the antisense strand to RISC and avoid side effects such as activation of immune response and sense strand misloading. Then, we describe the design of novel lipid, carbohydrate and peptide conjugates to enhance cellular uptake. Finally, we describe the use of nanostructures for drug delivery and for the controlled deposition of matter on surfaces. We invite the readers to submerge into a highly interdisciplinary discipline that combines organic chemistry, biochemical assays, pharmacology issues as well as materials chemistry and structural studies in order to increase the applications of nucleic acids.

The Regioselective Conjugation of the 15-nt Thrombin Aptamer with an Optimized Tripeptide Sequence Greatly Increases the Anticoagulant Activity of the Aptamer

“…In this respect, the development of aptamer conjugates is a highly in demand field of study as a way to improve the affinity or functional characteristics of aptamers [ 3 , 7 , 8 ]. Depending on the functional roles of subunits in the oligonucleotide conjugate, this may include lipids, carbohydrates, peptides, or some other functional elements [ 9 , 10 ]. Particularly, aptamer–peptide conjugates may exhibit improved precision of targeting, enhanced affinity [ 11 , 12 , 13 ], or better delivery [ 10 , 11 ] as compared to unmodified aptamers or unconjugated peptides.…”

Aptamer-Based Targeted Protein Degradation

“…First, upon entry into the body, aptamers are susceptible to degradation by nucleases that are widely available in the physiological environment and rapidly excreted through renal filtration . Chemical modification of aptamers can increase their nuclease resistance and improve their stability, most commonly by replacing 2′-OH with fluoro (F), amino (NH 2 ), or O-methyl (OCH 3 ) groups and by capping the 3′ end with inverted thymidine. , Sometimes multiple modifications are combined to achieve the best performance. However, chemical modifications may affect the folding structure of the initial aptamer, thus impairing the specific affinity of aptamer to its target, thus careful evaluation and optimization are required.…”

Nucleic Acid-Based Approaches to Tackle KRAS Mutant Cancers

“…Addressing acquired resistance in KRAS-driven tumors, which can emerge after treatment with KRAS-specific inhibitors, is another promising avenue for harnessing nucleic acidbased therapeutics. The significant impact of these chemical modifications on the pharmacokinetics and overall efficacy of oligonucleotide therapies has driven rapid progress in this field, as extensively reviewed in the literature [41,[104][105][106].…”