Mechanisms of Nucleoside Analogs and their Therapeutic uses in Viral Infections

Nucleoside analogs are among the most potent and widely used agents in Ä?nÆ?ŝÇ?ŝÆ?Ä?ů therapy. These ƐÇ?nÆ?Å?Ä?Æ?ŝc compounds mimic naturally occurring nucleosides, the building blocks of nucleic acids, but with structural mŽÄ?ŝĨŝcÄ?Æ?ŝŽnƐ that disrupt viral Æ?Ä?Æ?ůŝcÄ?Æ?ŝŽnÍ? By Æ?Ä?Æ?ŐÄ?Æ?ŝnŐ cÆ?ŝÆ?ŝcÄ?ů processes in viral life cycles, nucleoside analogs have Æ?Ä?Ç?ŽůƵÆ?ŝŽnŝÇ?Ä?Ä? the treatment of a variety of viral ŝnĨÄ?cÆ?ŝŽnƐÍ? including HIV, Å?Ä?Æ?Ä?Æ?ŝÆ?ŝƐ B and C and herpesviruses. This Ä?Æ?Æ?ŝcůÄ? describes the mechanisms by which nucleoside analogs inhibit viral Æ?Ä?Æ?ůŝcÄ?Æ?ŝŽnÍ? their Æ?Å?Ä?Æ?Ä?Æ?Ä?ƵÆ?ŝc Ä?Æ?Æ?ůŝcÄ?Æ?ŝŽnƐ and the challenges associated with their use. The primary mechanism of Ä?cÆ?ŝŽn for nucleoside analogs is their ability to interfere with viral Æ?Ä?Æ?ůŝcÄ?Æ?ŝŽnÍ? Once administered, these compounds are taken up by cells and phosphorylated by cellular or viral kinases to their Ä?cÆ?ŝÇ?Ä? triphosphate forms. In this Ä?cÆ?ŝÇ?Ä?Æ?Ä?Ä? state, nucleoside analogs are incorporated into the viral genome during Æ?Ä?Æ?ůŝcÄ?Æ?ŝŽnÍ? leading to chain Æ?Ä?Æ?mŝnÄ?Æ?ŝŽn or faulty Æ?Ä?Æ?ůŝcÄ?Æ?ŝŽn processes. Many nucleoside analogs lack a 3'- hydroxyl group, which is need for forming the phosphodiester bond required for Ä?ůŽnŐÄ?Æ?ŝnŐ DNA or RNA strands. When these analogs are incorporated into the growing nucleic acid chain, Æ?Ä?Æ?ůŝcÄ?Æ?ŝŽn halts. For example, zidovudine (AZT), a key Ä?nÆ?ŝÆ?Ä?Æ?Æ?ŽÇ?ŝÆ?Ä?ů drug, disrupts HIV Æ?Ä?Æ?ůŝcÄ?Æ?ŝŽn through this mechanism. Some nucleoside analogs introduce mƵÆ?Ä?Æ?ŝŽnƐ into the viral genome, leading to nonviable or Ä?Ç?ƐĨƵncÆ?ŝŽnÄ?ů progeny viruses. Ribavirin, used in Æ?Æ?Ä?Ä?Æ?ŝnŐ Å?Ä?Æ?Ä?Æ?ŝÆ?ŝƐ C, induces lethal mutagenesis in viral RNA.Nucleoside analogs can also act as cŽmÆ?Ä?Æ?ŝÆ?ŝÇ?Ä? inhibitors of viral polymerases, enzymes important for genome Æ?Ä?Æ?ůŝcÄ?Æ?ŝŽnÍ? Sofosbuvir, an analog used in Å?Ä?Æ?Ä?Æ?ŝÆ?ŝƐ C treatment, targets the viral RNA-dependent RNA polymerase, Æ?Æ?Ä?Ç?Ä?nÆ?ŝnŐ viral RNA synthesis. The ƐÄ?ůÄ?cÆ?ŝÇ?ŝÆ?Ç? of nucleoside analogs stems from their Æ?Æ?Ä?ĨÄ?Æ?Ä?nÆ?ŝÄ?ů Ä?cÆ?ŝÇ?Ä?Æ?ŝŽn or ŝncŽÆ?Æ?ŽÆ?Ä?Æ?ŝŽn by viral enzymes rather than host enzymes. This ƐÆ?Ä?cŝĨŝcŝÆ?Ç? reduces ŽĨĨͲÆ?Ä?Æ?ŐÄ?Æ? Ä?ĨĨÄ?cÆ?ƐÍ? making them highly Ä?ĨĨÄ?cÆ?ŝÇ?Ä? Æ?Å?Ä?Æ?Ä?Æ?Ä?ƵÆ?ŝc agents.

Author(s): Feng Duan

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