Galidesivir, an Adenosine Analog, Disrupts Viral RdRp Activity

By Edward Jenner 2021-10-19 #Adenosine, #COVID-19, #RdRp, #Yellow Fever

RdRp is a crucial viral enzyme in the life cycle of RNA viruses; hence, it has been targeted in various viral infections, including the HCV, the Zika virus (ZIKV), and coronaviruses (CoVs). The active RdRp site is highly conserved, with two successive and surface-accessible aspartates in a beta-turn structure. RdRp differs from RNA polymerase as it works to catalyze the synthesis of an RNA strand complementary to a given RNA template, rather than using a DNA template. Therefore, desirable characteristics for antiviral nucleosides include efficient uptake into cells and efficient conversion of the nucleoside to the triphosphate nucleotide by mammalian kinases.

Galidesivir (also known as BCX4430), an adenosine analog, is a direct-acting antiviral agent, which disrupts viral RNA-dependent RNA polymerase (RdRp) activity. Galidesivir is active in vitro against many RNA viral pathogens, including the filoviruses and emerging infectious agents such as MERS-CoV, SARS-CoV, and SARS-CoV-2. In addition, it also inhibits lethal infections with Ebola virus, Marburg virus, Rift Valley fever virus, and Yellow Fever virus. Moreover, Galidesivir inhibits viral RNA polymerase function, acting as a non-obligate RNA chain terminator. Cellular kinases phosphorylate BCX4430 to a triphosphate that mimics ATP; viral RNA polymerases incorporate the drug’s monophosphate nucleotide into the growing RNA chain, causing premature chain termination. Furthermore, Galidesivir triphosphate inhibits HCV RNA polymerase transcriptional activity and induces premature termination of RNA chain synthesis by HCV RNA polymerase.