T-705RTP is a Selective and GTP-Competitive Influenza Virus RNA Polymerase Inhibitor

The influenza virus is a serious threat to mankind for mankind. Influenza viruses enter the body, they bind to the sialic acid of glycoproteins on the cell surface. Then, they are endocytosed into the cell. Releasing virus RNA and RNA-bound protein complexes (RNP) into the cytoplasm (uncoating). RNP released into the cytoplasm enters the nucleus. Subsequently, they transcribe and replicate via the RNA-dependent RNA polymerase (RdRp) of the influenza virus.
Translated-virus proteins migrate with the nascent RNP to the cell surface. Lastly, Virus particles released from the cell membrane by neuraminidase.

In the past decades, conventional anti-influenza virus agents can prevent the proliferation processes of influenza viruses, such as oseltamivir and zanamivir. However, those agents also exhibit resistant viruses. Thus, it is extremely crucial to develop new anti-virus agents with different acting mechanisms. T-705 is a novel anti-influenza virus agent. It is different from the conventional anti-viruses agents and strongly exhibits strong inhibition for the replication of influenza virus types A, B, and C RNA viruses.

T-705 can be converted to T-705-4-ribofuranosyl-5-triphosphate (T-705RTP) by intracellular enzymes.

T-705RTP inhibits influenza virus RNA polymerase activity in a dose-dependent and a GTP-competitive manner. In addition, T-705RTP blocks the incorporation of ATP and GTP in a competitive manner with Ki values of 7.72 and 1.56 μM, respectively. The compound inhibits the incorporation of CTP in a mixed-type manner, exhibits a Ki value of 11.3 μM. At the same time, it inhibits the incorporation of UTP noncompetitively.

T-705RTP is a ribose phosphate intracellularly from T-705. It has a base moiety and natural ribose phosphate. The unnatural base of T-705RTP alters the hydrogen bond of the virus RNA base. As a result, T-705RTP incorporates into virus RNA strands and inhibits nucleic acid chain extension.

In conclusion, T-705RTP inhibits subsequent virus RNA extension. T-705RTP has potent antiviral activities against both influenza virus and RNA viruses. The investigation of the mechanism of T-705RTP on virus RdRp will devote to the development of new agents on the influenza virus.

Sangawa H, et al. Antimicrob Agents Chemother. 2013 Nov;57(11):5202-8.