Antisense approach

Several approaches are utilized to study systems biology. The bottom-up approach starts from the molecular level, the omics, to identify and evaluate the genomic and proteomic basis of diseases. The top-down approach attempts to integrate human physiology and diseases to provide models to understand disease pathways at organ levels. 

Another way is the intermediate method to bridge the two approaches above. This method determines biologically multiplexed activity profile data. It integrates biological complexity at multiple levels pathways, signal transductions, and environmental factors. 

Source Butcher EC, Berg EL, Kunkel EX Systems biology in drug discovery, Nature Biotechnology 22 1253-1259 (2004). 

Exhibit 3.14 provides a diagrammatic visualization of the approaches to tackle this new field of study. 

Genetic information is transcribed from the genes in the DNA to mRNA. The information is then translated from the mRNA to synthesize the protein (refer to Appendix 2). This process is depicted as follows  

Chapter 3 Drug Discovery Small Molecule Drugs 

---

The triplet-sensitized photorearrangement of allylphosphites [65- 67] offers a rapid and efficient access (60-70% yields) to oligonucleotides, which are key molecules in the antisense approach to antiviral and antitumor therapy (Scheme 40) [39,40,73]. 

Figure 14.13 Overview of the concept of the antisense approach the end goal is the prevention of expression of a particular gene product (invariably a protein) by either blocking the transcription or translation of that gene...

Antisense Approach This is a relatively new approach and it requires modifications to oligonucleotides that can bind to RNA and DNA (refer to Appendix 2 for a description of cell structure, genes, DNA, RNA, and proteins). The antisense drugs are used to stop transcriptional (from DNA) or translational (from RNA) pathways from proceeding, and so interfere with the process of disease. 

The antisense approach is use of nucleic acids to reduce the expression of a specific target gene. As shown in Figure 58.2, a small piece of DNA, an oligodeoxynu-cleotide that is in the reverse orientation (antisense) to a portion of a target messenger RNA (mRNA) species, is introduced into a cell and a DNA-RNA duplex is formed by complementary Watson-Crick base pairing. Cessation of protein synthesis then may result from the rapid... 

Antisense approaches for knock-down of pain relevant genes... 

The antisense approach to pharmaceuticals is conceptually attractive and powerful. If a protein target and its sequence are known, then the sequence of the corresponding mRNA will also be largely known. If the exact mRNA sequence can be determined, then a complementary polynucleotide may be prepared to form a duplex. Longer complementary antisense strands give a more stable duplex. 

Paul D, Yao D, Zhu P, Minor LD, Garcia MM. 5-Hydroxytryptamine3 (5-HT3) receptors mediate spinal 5-HT antinociception an antisense approach. J Pharmacol Exp Ther 2001 298(2) 674-678. 

Synthetic oligonucleotides are being developed to target defined sites on DNA sequences or genes (double-strand DNA triplex approach) or messenger RNA (antisense approach) so that the production of disease-related proteins is blocked. These oligonucleotides offer prospects of treatment for cancers and viruses without harming healthy tissues.8,9... 

---