Parallels with known anti-viral mechanisms could be informative; however after 40 years, these are not entirely clear
• Ribavirin (1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) is an artificial guanosine nucleoside analogue with broad-spectrum antiviral properties that was first synthesized in 1972 ( Table 1; ref
1
Although its mechanism of action is a matter of debate, several possibilities have been proposed, including depletion of guanine nucleotides through inhibition of inosine monophosphate dehydrogenase (IMPDH)
g
Perhaps most intriguing is the discovery that mutations in IMPDH are associated with hereditary retinal disease 7 - 9
Virology 2003; Ribavirin specifically binds to the substrate-binding site of the IMPDH enzyme limiting access of the enzyme to its endogenous substrate (inosine-5-monophosphate) ultimately leading to the decreased synthesis and lower levels of GTP
Interestingly, an uncompetitive IMPDH inhibitor, mycophenolic acid (MPA), exerted more potent antiviral effect again PPRV
Ribavirin is a unique guanosine analog with broad-spectrum activity against many RNA and DNA viruses
Ribavirin, when co-administered with IFNα, substantially improves the efficacy of the therapy, achieving 40% sustained virological response (SVR) in previously untreated patients, in contrast to ∼13% with IFNα alone
This inhibitor binds to the nicotinamide binding portion of the cofactor-binding site, after NADH but before XMP is released from the The RMP form (which is only about 10% of the ribavirin metabolites ), binds IMPDH
Binds to and redistributes mammalian eIF4E from the nucleus to the cytoplasm (K ~ 0
Ribavirin reduced HCV replicon colony-forming efficiency (CFE) in a dose-dependent fashion, suggesting Ribavirin and MPA can bind IMPDH directly at different sites and interfere the catalytic reaction through different mechanisms [24]
The RMP form (which is only about 10% of the ribavirin metabolites [24]), binds IMPDH [25]
One such inhibitor is mycophenolic acid (MPA)
Ribavirin or IFN-α treatment did not increase or decrease the expression of IMPDH level IFN-α binds to the cell surface receptor, which activates the cellular Jak-Stat pathway leading to the activation of PKR
Thus, differences in the structures of these drugs, and their metabolized forms, likely underlie their Several small molecule compounds bind to the HIV co-receptors CCR5 or CXCR4 and prevent HIV from using these proteins in the entry process
[Google Scholar] Articles from Applied Microbiology and Ribavirin, a broad-spectrum antiviral agent is used in the clinic alone or in combination with other antivirals and/or interferons
The most important IMPDH inhibitors are Mycophenolic acid (MPA), Mizoribine, Ribavirin (RBV) and Tiazofurin adenine dinucleotide (TAD)
These data suggest that inhibition of guanine synthesis alters spermidine Ribavirin, a broad-spectrum antiviral agent is used in the clinic alone or in combination with other antivirals and/or interferons
IMPDH is an essential enzyme in GTP synthesis where it converts IMP to XMP (Figure 1A)
The most important IMPDH inhibitors are Mycophenolic acid (MPA), Mizoribine, Ribavirin (RBV) and Tiazofurin adenine dinucleotide (TAD)
1016/S0042-6822(03)00152-1 Corpus ID: 26961779; The effect of ribavirin and IMPDH inhibitors on hepatitis C virus subgenomic replicon RNA
Reyes}, journal={Virology Early studies showed that IMPDH inhibitors, such as mycophenolic acid or ribavirin, cause rapid formation of IMPDH filaments in cultured cells (20, 22, 28)
Inosine monophosphate dehydrogenase (IMPDH) of human is an attractive target for immunosuppressive agents
In order to be active, benzamide riboside has to be converted to BAD, an NAD analogue that binds to the NAD site on IMPDH
2019; de Souza et al
Depriving cells of essential purine precursors by limiting glutamine ( 29 ) or folate derivatives supplied by the thymidylate cycle ( 30 ) likewise cause IMPDH to polymerize
Ribavirin (1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) is an artificial guanosine nucleoside analogue with broad-spectrum antiviral properties that was first
Ribavirin and mycophenolic acid (MPA) are known inhibitors of the IMPDH enzyme (E
Ribavirin (RBV) is a most commonly used in the (HCV) infection
Ribavirin: a drug active against many viruses with multiple effects on virus replication and propagation
of ribavirin have been developed, among them tiazofurin, which is inactive against viruses but is a potent anticancer drug
X-ray crystal structures of mycophenolic acid (MPA) ( 26 ), ribavirin monophosphate ( 27 ), and an IMP analogue together with an NAD analogue ( 3) in complex with IMPDH have
Ribavirin is a synthetic nucleoside analog and known inhibitor of IMPDH enzyme
This makes the IMPDH-inhibitory form of ribavirin a minor intracellular component
Thus, differences in the structures of these drugs, and their metabolized forms, likely underlie
Pharmacology
The first and second groups occupy the binding positions of IMP and NAD sites, respectively
Pharmacological studies have shown that early ribavirin exposure assessed by the area under the curve (AUC) at day 0 and ribavirin trough concentration during the first three months of therapy Bateman domains bind adenosyl compounds
As previously mentioned, ribavirin can specifically bind to the substrate-binding site of the IMPDH enzyme, limiting access of the enzyme to its endogenous substrate inosine-5 Furthermore, IMPDH is an essential enzyme in the biosynthesis of guanine nucleotide, that its inhibitors have revealed proven effects against human coronaviruses , was the last selected target in this represented molecular docking studies since NR shows the same structural pattern with one major group of IMPDH inhibitors including Ribavirin
Inosine monophosphate dehydrogenase ( IMPDH) and cytidine triphosphate synthase ( CTPS) are two metabolic enzymes that perform rate‐limiting steps in the de novo synthesis of purine and pyrimidine nucleotides, respectively
A study on the regulation of IMPDH with mycophenolic acid (MPA) showed that MPA binds to IMPDH and causes a conformational change resulting in the formation of inactive angular aggregates
As IMPDH is a key enzyme in purine nucleotide synthesis, supplementation of exogenous guanosine attenuate the anti-PPRV effect of ribavirin
Medullar regeneration is partially prevented by various degrees of bone marrow To confirm IMPDH involvement in response to ribavirin treatment, we performed a rescue experiment where CNE-2 cells were simultaneously treated with ribavirin (50 μmol/L) and guanosine (50 μmol/L), hypothesizing that repleting guanine nucleotide pools would alter the effect of ribavirin on NPC cells
Finally, the third group ligands binds to allosteric-site that is far from the IMP and NAD pockets (Shu and Nair, 2008)