Abstract
Therapeutics that inhibit enzymes, receptors, ion channels, and cotransporters have long been the mainstay of cardiovascular medicine. Now, oligonucleotide therapeutics offer a modern variation on this paradigm of protein inhibition. Rather than target a protein, however, small interfering ribonucleic acids and antisense oligonucleotides target the messenger RNA (mRNA) from which a protein is translated. Endogenous, cellular mechanisms enable the oligonucleotides to bind a selected sequence on a target mRNA, leading to its degradation. The catalytic nature of the process [...]
Highlights
Almost every drug targets a protein, the last step in the flow of genetic information from DNA through transcription and translation
After cleaving the messenger RNA (mRNA), the antisense strand remains bound to the enzyme; in the catalytic action of small interfering ribonucleic acid (siRNA), a single molecule serves to cleave a large number of target mRNAs
The results indicate that, if approved, inclisiran has the potential to be a novel, safe, effective approach to treating hypercholesterolemia in high-risk patients
Summary
Almost every drug targets a protein, the last step in the flow of genetic information from DNA through transcription and translation. ASOs are single-stranded oligonucleotides of 15-20 bases, designed to be complementary (antisense) to a target site on the mRNA transcript,[6,7] to which they bind via Watson–Crick base pairing. The sense “passenger” strand is ejected, and the antisense “guide” strand remains loaded and “guides” the RISC to a complementary site on the target mRNA, where it binds through Watson–Crick base pairing.[8] After cleaving the mRNA, the antisense strand remains bound to the enzyme; in the catalytic action of siRNAs, a single molecule serves to cleave a large number of target mRNAs. In this review, key technical advances in the evolution of oligonucleotide therapeutics, including ASOs and siRNAs approved or in late-stage clinical development for cardiovascular diseases, are discussed
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