Oligonucleotide-Based Drugs and Therapeutics by Nicolay Ferrari download in iPad, pdf, ePub
Ferrari is the co-inventor of six patents.
The methyl phosphonate group is not stable to aqueous base, so the protecting groups on the heterocyclic bases have to be cleavable under mild conditions. Antisense oligonucleotides Viruses and bacteria have unique proteins that are essential for their survival. Methyl phosphonates also have a detrimental effect on the aqueous solubility of the antisense oligonucleotides because the backbone is uncharged. This is not an ideal situation from a pharmaceutical standpoint, but it has not prevented regulatory bodies from allowing antisense oligonuclotides to be used in the clinic.
Molecules that can either facilitate quadruplex formation or stabilize quadruplexes have the potential to interfere with replication, inhibit telomerase activity and arrest cancer cell growth. There are only two copies of genetic information in the nucleus of the human cell, and, even in the case of genes that occur in tandem, only a handful of copies normally exist.
It is therefore necessary to chemically modify antisense oligonucleotides to make them stable in cells. In the case of phosphorothioates this is due to the steric bulk of the sulfur atoms which interferes with duplex formation.
Antiparallel triplexes are intrinsically unstable at all pH values. It could also be used to develop a new class of drugs that offer high specificity and a rapid response.
This means that telomerase may be a good target for novel antitumour agents. This is a major task but it is not insurmountable. However, it has proved difficult to develop compounds with the ability to eliminate viruses entirely or to prevent their integration into the host genome. Nature offers us clues to solving the problem.
This is probably a process that has evolved to define the useful lifetime of a cell. These bonds are called Hoogsteen bonds. Fortunately, some cells take in oligonucleotides by a process known as receptor-mediated endocytosis, which involves the specific uptake of the oligonucleotide by natural cell-surface receptors. The resulting plants had variegated petals, indicating that gene expression had been affected. For this reason a number of oligonucleotide-based approaches are now being developed.
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