Dr. Muhammad Torequl Islam :
Favipiravir (also called avigan, favilavir, favipira, T-705), a pyrazinecarboxamide derivative was discovered by chemical modification of a pyrazine analog. To date, it has been found to act against a number of viruses, including several types of Influenza, Ebola, Rabies, Human metapneumovirus, Respiratory syncytial virus, Zika virus, Chikungunya, Polio, Rhino, Enterovirus 71 and Noro. But, there is no record for its anti-coronavirus activity. Recent evidence suggests that this drug undergoes following clinical trails: (start and end date)
1. March 25, 2020 to July 2020
2. March 8, 2020 to May 2020
3. April 15, 2020 to November 30, 2020
4. April 1, 2020 to September 15, 2020
The exact mechanism of interaction of favipiravir ribofuranosyl-5′-triphosphate (favipiravir-RTP) with RNA-dependent RNA polymerase (RdRp) molecule is yet to be elucidated. It is hypothesized that favipiravir has virucidal effects, and it may be misincorporated in a nascent viral RNA, or it may act by binding to conserved polymerase domains, thus preventing incorporation of nucleotides for viral RNA replication and transcription.
It is demonstrated that favipiravir induced lethal mutagenic effect on influenza virus. It is a prodrug that is metabolized to its active form, favipiravir-ribofuranosyl-5′-triphosphate (favipiravir-RTP). Unlike an RNA virus, humans do not have RdRp, but have DNA-dependent RNA polymerase (DdRp) and DNA-dependent DNA polymerase. Favipiravir-RTP was tested for the inhibition of those polymerase activities.
Favipiravir-RTP inhibited influenza RdRp with an IC50 of 0.341 µM/L, but did not human DNA polymerases a, ß, ? at up to 1000 µM/L. Furthermore, in a study, it slightly inhibited human RNA polymerase II, which belongs to DdRp.
Human hypoxanthine guanine phosphor ribosyl transferase (HGPRT) is believed to play a key role in its activation process. HGPRT is an enzyme encoded in humans by the HPRT1 gene that catalyzes conversion of hypoxanthine to inosine monophosphate and guanine to guanosine monophosphate. This reaction transfers the 5-phosphoribosyl group from 5-phosphoribosyl 1-pyrophosphate to the purine. HGPRT plays a key role in the generation of purine nucleotides through the purine salvage pathway. Partial deficiency of the HGPRT is also called Kelley-Seegmiller syndrome (a rare genetic disorder manifesting as a gout-urolithiasis) and results glucose 6-phosphate dehydrogenase deficiency and phosphoribosylpyrophosphate (PRPP) synthetase superactivity. During lung cancer this enzyme has been seen to increase in non-small-cell lung cancer cell lines A549 and NCI-H460 cell lines.
Lesch-Nyhan syndrome (LNS) is a rare inherited disorder caused by a deficiency of the HGPRT. It is due to mutations in the HPRT1 gene on the X chromosome. The HGPRT deficiency increases uric acid in our body fluids. The combination of increased synthesis and decreased utilization of purines leads to high levels of uric acid production, results severe gout and kidney problems, poor muscle control and moderate intellectual disability
Therefore, how effective this hopeful drug will be in the patients having a deficiency or mutation of HGPRT enzyme, especially who have Kelley-Seegmiller syndrome, Lesch-Nyhan syndrome, myocardial ischemia, hyperuricemia, megaloblastic anemia, glucose 6-phosphate dehydrogenase deficiency, and phosphoribosylpyrophosphate (PRPP) synthetase superactivity. Moreover, it has broad-spectrum virucidal effects along with the mutagenic (on viral cell) and an inhibitory effect on human RNA polymerase II which belongs to DdRp.
So, adequate research is urgently needed regarding its toxicogenetic profile (i.e., toxicity, cytotoxicity, genotoxicity and mutagenicity), unless host genomic safety and stability in the case of its long-term use should be questionable matter. In 2014, favipiravir was approved in Japan to treat influenza pandemics, although its effectivity in primary human airway cells is still controversial.
(Dr. Muhammad Torequl Islam, Assistant Professor, Department of Pharmacy, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj; email: [email protected])
