Research Article - Journal of Clinical and Bioanalytical Chemistry (2021) Volume 5, Issue 4
Favipiravir is a broad spectrum antiviral prescription famouus to selectivity block RNA-Dependent RNA Polymerase (RDRP) and sars-COVID-19.
A Mohamed Sikkander*
Department of Chemistry, Velammal Engineering College, Chennai, India
- *Corresponding Author:
- Dr. A Mohamed Sikkander
Department of Chemistry Velammal Engineering College Chennai India
Accepted Date: 17 June, 2021
Background: This study was aimed at assessing the magnitude of induced abortion and associated factors among students in Hawassa University, southern region, Ethiopia, 2019.
Research and Methods: Favipiravir (6-fluoro-3-hydroxy-2-pyrazinecarboxamide), or else known as “T-705, or Avigan” has shown enormous covenant of antiviral activity against many of RNA viruses. Scientists have conducted rigorous studies on its antiviral properties against wide range of RNA viruses such as influenza, West Nile, and Ebola viruses together in vitro and in vivo. Yet, favipiravir has also enthused hopes that it may provide humankind with a broad spectrum of antivirals which may have a lesser amount of toxicity and elevated potency at little doses. India-based Glenmark Pharmaceuticals has reported constructive top-line data from a Phase III clinical trial of its favipiravir nonspecific FabiFlu to delicacy mild to moderate COVID-19.
Result and Discussion: The open-label, randomised, multi-centre examinations assessed the wellbeing and efficiency of Fabi Flu plus standard loyal care compared to standard compassionate care alone in a total of 150 patients at seven sites across India. It is a broad spectrum antiviral medicine known to specific block RNA-dependent RNA polymerase (RDRP) and SARS-CoV-2 viral imitation phase. Examine patients in the favipiravir arm established a 3,600 mg dose on day one, followed by 1,600 mg for up to 14 days, along with typical compassionate care.
Conclusions: Data exposed arithmetical improvements on the most important efficacy endpoint. A 28.6% faster viral consent was pragmatic in the overall population on Glenmark’s treatment versus those in the have power over group. Results also showed a statistically noteworthy more rapidly time to clinical improvement. On key resulting outcomes for clinical enhancement, favipiravir established a 40% faster ‘clinical cure’, distinct as normalisation of clinical signs with a statistically momentous reduce in median time to clinical cure.
RNA polymerase, Clinical cure, COVID-19, Ebola virus, Influenza, Lassa virus, RNA polymerase activity.
Favipiravir is a customized pyrazine analog that was originally permitted for therapeutic use in resistant cases of influenza. The antiviral targets RNA-reliant RNA polymerase (RDRP) enzymes, which are essential for the record and copying of viral genomes. Favipiravir control copying of influenza A and B, but the drug has shown assure in the treatment of avian influenza, and may be a substitute option for influenza strains that are opposed to to neuramidase inhibitors.
Research and Methods
Favipiravir has been investigated for the treatment of severe pathogens such as Ebola virus, Lassa virus, and at the moment COVID-19. Favipiravir is an oral antiviral permitted for the treatment of influenza in Japan. It selectively inhibits RNA polymerase, which is required for viral replication. Japan has commenced with a phase 3 clinical trails. In USA, a phase 2 trial will sign up approximately 50 patients with COVID-19, in teamwork with Brigham and Women's Hospital, Massachusetts General Hospital, and the University of Massachusetts Medical School. In India, a phase 3 trial combined 2 antiviral agents, favipiravir and umifenovir, started. (Figure 1).
Methods and Materials
Synthesis and structure elucidation of favipiravir
Favipiravir was initialy synthesized from an inexpensive and commercially available starting material, 2-aminopyrazine. The preferential route well-established within consisted of seven steps, and was highlighted by the novel and efficient synthesis of 3, 6-dichloropyrazine-2-carbonitrile. This transitional was organized in four successive steps which were regioselective chlorination of the pyrazine ring, bromination, Pd-catalyzed cyanation, and Sandmeyer diazotization/chlorination. This etiquette eliminated the hazardous POCl3 of previous synthetic methods and offered a better yield (48%) which was 1.3-fold higher than a newly available procedure. From transitional, the succeeding nucleophilic fluorination, nitrile hydration and hydroxyl substitution competently afforded the target product. One more synthetic approach with the same starting material was also investigated to bypass the allergy-causing dichloro intermediate.
Favipiravir (T-705) is a novel anti-influenza drug which functions to selectively reduce the RNA-dependent RNA polymerase of influenza virus.
T-705 ribofuranosyl triphosphate is the vigorous form, generated from the parent drug by a series of intracellular enzymes. Favipiravir too displays inhibitory actions against a number of other pathogenic RNA viral infections, for instance arenavirus, bunyavirus, flavivirus, alphavirus, and norovirus.
In addition, it is supposed to be a promising therapeutic candidate for Ebola virus infection. In a demonstration clinical study during the outbreak of Ebola virus, patients who received T-705 had a significant viral consignment lessening compared with the control group.
In recent times, favipiravir and related structures have paying attention extensively in the pharmacology field of antiviral and antiparasitic research (Figure 2).
Result and Discussion
Rhinovirus RNA polymerase
Favipiravir (T-705) is an antiviral medicine that selectively subdued the RDRP of influenza virus. It showed accurate activity alongside all three influenza A, B, and C. It also passive the RV copying in HeLa cells, with an EC50 of 29 μg/mL. Analysis showed that the most important mechanism of action of favipiravir against the influenza virus was specific inhibition of vRNA polymerase. It is predicted that a comparable mechanism might occur with other viruses, such as PV and RV, subdued by favipiravir, which may account for its broad-spectrum embarrassment. Mechanistic studies give you an idea about that the favipiravir and its form favipiravir-RMP (favipiravir-ribofuranosyl-50-monophosphate) do not restrain influenza RNA polymerase activity, but it is the phosphoribosylated form, favipiravir-ribofuranosyl-50- triphosphate (RTP) that inhibits the enzyme. Metabolism of favipiravir to its triphosphate form occurs in an extracellular milieu in a concentration-dependent method. The vRNA polymerase erroneously recognizes favipiravir-RTP as a purine nucleotide. This favipiravir-RTP is misincorporated in budding vRNA, or it may act by obligatory to conserved polymerase domains, preventing assimilation of nucleotides for vRNA replication and transcription.
Structure–function relationship of negative-stranded viral RNA polymerases
In addition, researchers have also shown that the RABV multiplication in neuro-2a cells was restricted by the addition of T-705. Unlike ribavirin (1-(β-D-ribofuranosyl)-1,2,4- triazole-3-carboxamide) whose constrained clinical use is due to its limited efficacy and its administration also causes reduction in intracellular Guanosine Triphosphate (GTP) pools which ultimately leads to hemolytic anemia in patients.
Favipiravir/ribavirin alliance antiviral commotion is now being explored by researchers against two bunyaviruses, i.e., CCHFV and Rift Valley fever virus. In cooperation of these drugs have shown direct antiviral activity against viral RNA polymerases but their synergistic mechanism is not yet clear. Ribavirin enhances the action of favipiravir by its tortuous action on proposed immunomodulatory activities and Inosine-5′- Monophosphate Dehydrogenase (IMPDH) inhibition.
The RNA polymerase inhibitor favipiravir (T-705) is a broad- spectrum antiviral candidate drug with commotion against a number of RNA viruses, togetherith arenavirus, bunyavireses, flaviviruses like West Nile virus, and yellow fever virus, over and above influenza A and B viruses. Favipiravir induces a speedy mutation rate of the virus RNA polymerase complex, which consequences in a large proportion of nonviable viruses within the total virus population (Figure 3).
Such “error catastrophe” was until that time also observed for the broad-spectrum antiviral ribavirin. In poliovirus, ribavirin- induced fortification of the virus quasispecies was found to affect the pathogenicity of the virus in mice. On the other hand, the employ of ribavirin to treat influenza is debatable when considering clinical profit and the substantial side effects. Reports on ribavirin antiviral confrontation are uncommon, but confrontation has been reported, for instance, for hepatitis C- and enteroviruses. No influenza antiviral confrontation to favipiravir has been reported so far.
Favipiravir was discovered by phenotypic screening against influenza virus at Research Laboratories .Further studies to examine the mechanism of actions, and anti-viral effects against various types of viruses. Favipiravir is phosphoribosylated in the cells to be an dynamic form, favipiravir-RTP, which is recognized as a purine nucleotide by RDRP, and inhibits the RDRP enzyme action. Favipiravir-RTP exhibits no belongings on DNA-dependent RNA or DNA polymerases. These typescript explain that favipiravir favors RNA virus over DNA virus and mammalian cells. Favipiravir is effectual in multiple types of Influenza viruses, regardless of sensitive or resistant to existing anti-influenza drugs. Of specific note is that favipiravir is active against an extensive range of other RNA viruses in vitro and in vivo. Facts to date from clinical studies show that favipiravir is well tolerated in human.
• Favipiravir is phosphoribosylated in the cells to be an dynamic form, favipiravir-RTP, which is recognized as a purine nucleotide by RdRp, and inhibits the RdRp enzyme action. Favipiravir-RTP exhibits no belongings on DNA-dependent RNA or DNA polymerases.
• Favipiravir is effectual in multiple types of Influenza viruses, regardless of sensitive or resistant to existing anti-influenza drugs.
• Favipiravir is a pyrazinecarboxamide derivative with bustle against RNA viruses.
• Favipiraviris renewed to the ribofuranosyltriphosphate derivative by congregation enzymes and selectively inhibits the influenza viral RNA-dependent RNA polymerase.
• Yet, favipiravir has also enthused hopes that it may provide humankind with a broad spectrum of antivirals which may have a lesser amount of toxicity and elevated potency at little doses.
• The open-label, randomised, multi-centre examinations assessed the wellbeing and efficiency of FabiFlu plus standard loyal care compared to standard compassionate care alone in a total of 150 patients at seven sites across India. It is a broad spectrum antiviral medicine known to specific block RNA-dependent RNA polymerase (RDRP) and SARS-CoV-2 viral imitation phase.
• Examine patients in the favipiravir arm established a 3,600 mg dose on day one, followed by 1,600 mg for up to 14 days, along with typical compassionate care. Data exposed arithmetical improvements on the most important efficacy endpoint.
• Results also showed a statistically noteworthy more rapidly time to clinical improvement. On key resulting outcomes for clinical enhancement, favipiravir established a 40% faster ‘clinical cure’, distinct as normalisation of clinical signs with a statistically momentous reduce in median time to clinical cure.
- Shiraki K, Daikoku K. Favipiravir an anti-influenza drug against life-threatening RNA virus infections. Pharmacol Ther. 2020;209:107512.
- Smee D, Tarbet B, Furuta Y, et al. Synergistic combinations of favipiravir and oseltamivir against wild-type pandemic and oseltamivir-resistant influenza A virus infections in mice. Future Virol. 2013;8:1085-94.
- Furuta Y, Gowen BB, Takahashi K, et al. Favipiravir (T- 705), a novel viral RNA polymerase inhibitor. Antiviral Res. 2013;100:446-54.
- Fang Q, Wang D. Advanced researches on the inhibition of influenza virus by Favipiravir and Baloxavir. Biosafety and Health. 2020;2. Toots M, Plemper RK. Next-Generation Direct-Acting Influenza Therapeutics. Trans Res. 2020;220.
- Toots M, Plemper RK. Next-Generation Direct-Acting Influenza Therapeutics. Trans Res. 2020;220.
- Liu G, Wong G, Su S, et al. Clinical Evaluation of Ebola Virus Disease Therapeutics. Trends Mol Med. 2017;23:820-30.
- Kelvin KW, Yuen KY, Cheung NN, et al. Mycophenolic acid, an immunomodulator, has potent and broad-spectrum in vitro antiviral activity against pandemic, seasonal and avian influenza viruses affecting humans. J Gen Virol. 2016;97:1807-17.
- Jin Z, Smith LK, Kim B, et al. The ambiguous base-pairing and high substrate efficiency of T-705 (Favipiravir Ribofuranosyl 5'-triphosphate towards influenza A viruspolymerase. PLoS One. 2013;8:e68347.
- Westover JB, Sefing EJ, Bailey KW, et al. Low-dose ribavirin potentiates the antiviral activity of favipiravir against hemorrhagic fever viruses. Antiviral Res. 2016;126:62-8.
- Delang L, Segura Guerrero NA, Tas A, et al. Mutations in
- the chikungunya virus non-structural proteins causeresistance to favipiravir (T-705), a broad-spectrum antiviral. J Antimicrob Chemother. 2014;69:2770-84.
- Andersen KG, Rambaut A., Lipkin WI, et al. The proximal origin of SARS-CoV-2. Nature Medicine. 2020;26:450– 452.