Dideoxynucleosides

Dideoxynucleosides are a class of nucleoside analogs that play a significant role in molecular biology and medicine, particularly in antiviral therapies and DNA sequencing. Structurally, they resemble natural deoxynucleosides but lack a hydroxyl group at the 3' carbon position of the sugar moiety. This missing 3' hydroxyl group is crucial because it serves as the attachment point for the next nucleotide during DNA synthesis.

When dideoxynucleosides are incorporated into a growing DNA chain by DNA polymerase, the absence of the 3' hydroxyl group prevents the addition of any further nucleotides. This effectively terminates DNA chain elongation, a phenomenon known as chain termination. This principle is the basis for their application in DNA sequencing methods, such as the Sanger sequencing technique, where dideoxynucleotides labeled with different fluorescent dyes are used to generate DNA fragments of varying lengths, allowing for the determination of the nucleotide sequence.

In a therapeutic context, certain dideoxynucleoside analogs are potent antiviral agents, especially against retroviruses like HIV. Once inside a cell, these analogs are phosphorylated to their triphosphate forms, which are then recognized by the viral reverse transcriptase enzyme. Upon incorporation into the viral DNA, they cause chain termination, inhibiting the replication of the virus. Examples of such drugs include zidovudine (AZT) and lamivudine. However, their use can be associated with toxicities, often related to mitochondrial dysfunction due to the inhibition of cellular DNA polymerases.