Nucleotideanalogen

Nucleotideanalogen (often written nucleotide analogue) is a class of compounds closely resembling natural nucleosides or nucleotides but bearing modifications to the base, sugar, or phosphate groups. These alterations generally allow the molecule to be recognized by cellular or viral polymerases and incorporated into nucleic acids, where they disrupt replication, transcription, or repair processes.

Activation and metabolism: Many nucleotideanalogs require phosphorylation by cellular kinases to form active triphosphate or other active forms; some are administered as prodrugs to improve bioavailability and tissue delivery.

Mechanisms of action: Incorporated analogs can terminate chain elongation if they lack the 3' hydroxyl group, act as competitive inhibitors of polymerases, cause lethal mutagenesis by mispairing, or inhibit nucleotide synthesis enzymes, thereby impeding nucleic acid production.

Applications: Nucleotideanalogs are used as antiviral agents against herpesviruses, HIV, HCV, HBV, and other viruses, and as anticancer drugs (examples include gemcitabine and 5-fluorouracil). They also serve as valuable research tools in molecular biology, notably as chain-terminating nucleotides in DNA sequencing and as inhibitors in PCR.

Notable examples: Acyclovir, ganciclovir, zidovudine (AZT), lamivudine, entecavir, tenofovir, ribavirin, remdesivir, sofosbuvir, gemcitabine, cytarabine, and 5-fluorouracil.

Limitations and risks: Resistance can arise via mutations in viral or cellular polymerases or enhanced exonuclease activity. Toxicity may affect rapidly dividing cells (bone marrow suppression, gastrointestinal symptoms) and mitochondria, contributing to organ-specific adverse effects.