19-03-2011, 09:36 AM
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What is the antisense oligonucleotides?
The term antisense oligonucleotides refers to molecules made of synthetic genetic material, which interact with natural genetic material (DNA or RNA) harboring the information for production of proteins.
Antisense Oligonucleotides are unmodified or chemically modified ssDNA, RNA or their analogs. They are 13-25 nucleotides long and are specifically designed to hybridize to the corresponding RNA by Watson-Crick binding
History
The first clear enunciation of the concept of exploiting antisense compounds as therapeutic agents was in the work of Zamecnik and Stephenson in 1978
The revolution in the availability of viral and human genomic sequences enhanced the development of the antisense technology.
Over the past decade, substantial development in antisense science and manufacturing led to the approval of the first antisense drug fomivirsen (VitraveneTM) for the treatment of AIDS-related CMV retinitis
Fomivirsen (VitraveneTM)
In the meantime up to 50 new antisense compounds have entered phase I/II, and in some cases phase III trials
Mechanism of Action of Antisense Oligonucleotides.
Ribozymes
Ribozymes are RNA molecules that catalyze biochemical reactions
Ribozymes cleave single-stranded regions in RNA through transesterification or hydrolysis reactions that result in cleavage of phosphordiester bonds
Hammerhead Ribozymes
Identification of the minimum ribozyme structure and introduction of chemical modifications that retain ribozyme activity and enhancing stability to nucleases.
RNA Interference (RNAi)
– RNAi is an innate cellular process that directs the degradation of mRNA homologous to short double stranded RNA (dsRNA),
Limitations of Practical Applications of Antisense Oligonucleotides
Despite the simplicity of the idea behind the Antisense, several problems have to be overcome for successful application:
1. Accessible sites of the target RNA for oligonucleotide binding have to be identified
2. Antisense agents have to be protected against nucleolytic attack
3. Cellular uptake and correct intracellular localization
Medicinal Chemistry of Antisense Oligonucleotides
One of the major challenges for antisense approaches is the stabilization of oligonucleotides, as unmodified oligodeoxynucleotides are rapidly degraded in biological fluids by nucleases
Modifications of Nucleobases
1. Modifications that enhance base stacking by expanding the p-electron cloud are represented by lipophilic modifications in the 5 position of pyrimidines and the 7 position of 7-deaza-purines
