“…ConA-induced VLI model rats were intravenously (n = 4) or orally (n = 4) administered a single injection of CdG (1 mg/kg), which was synthesized as reported previously. 5) Blood samples (250 µL) were collected from the femoral vein using a heparinized syringe at 3, 15, 30, 45, 60, 90 and 180 min after intravenous administration and at 5, 15, 30, 45, 60, 90 and 180 min after oral administration. The blood samples were centrifuged at 3,000 rpm for 10 min to obtain plasma.…”
Section: Methodsmentioning
confidence: 99%
“…Our group has searched for novel NAs with antiviral activity against not only wild-type HBV but also HBV that is resistant to the currently marketed NA preparations. 4,5) As a result of screening of over 100 NAs in a real-time HBV-PCR assay, we identified a candidate compound, 4′-cyano-2′deoxyguanosine (CdG, Chart 1), which showed superior antiviral activity against ADV-resistant HBV (HBV A181T/N236T ) and ETV-resistant HBV (HBV L180M/S202G/M204V ) to ADV and ETV, respectively. 4) In addition, a study of the pharmacokinetics of CdG in healthy rats showed that CdG possessed favorable pharmacokinetic properties for use as an oral NA preparation against HBV infections with good bioavailability and a high distribution to the liver.…”
A nucleoside analog, 4′-cyano-2′-deoxyguanosine (CdG), which was developed as an inhibitor of the chronic hepatitis B virus (HBV), exhibited a superior antiviral activity against both wild-type and drugsresistant HBV to marketed nucleoside analogs. In addition to previous pharmacokinetic studies of CdG in healthy rats, this study reports on an evaluation of the pharmacokinetic characteristics of CdG in a rat model of viral liver injury (VLI) induced by treatment with concanavalin A. Following an intravenous administration of CdG at a dose of 1 mg/kg, the plasma concentration profile of CdG in VLI model rats was found to be similar to that of healthy rats with no significant difference in kinetic parameters. However, when CdG was orally administered at a dose of 1 mg/kg, the maximum blood concentration was much lower in VLI model rats than in healthy rats. Interestingly, the amount of residual food in the stomachs in VLI model rats was significantly larger than that in healthy rats, indicating that the adsorption of CdG in the gastrointestinal tract was inhibited in the presence of food as well as other marketed nucleoside analogs. As observed in healthy rats, CdG was largely distributed to the liver compared to the kidney in the VLI model. These results suggest that liver pathology has only a minor effect on the pharmacokinetic properties of CdG, but the influence of food on CdG absorption needs to be considered.
“…ConA-induced VLI model rats were intravenously (n = 4) or orally (n = 4) administered a single injection of CdG (1 mg/kg), which was synthesized as reported previously. 5) Blood samples (250 µL) were collected from the femoral vein using a heparinized syringe at 3, 15, 30, 45, 60, 90 and 180 min after intravenous administration and at 5, 15, 30, 45, 60, 90 and 180 min after oral administration. The blood samples were centrifuged at 3,000 rpm for 10 min to obtain plasma.…”
Section: Methodsmentioning
confidence: 99%
“…Our group has searched for novel NAs with antiviral activity against not only wild-type HBV but also HBV that is resistant to the currently marketed NA preparations. 4,5) As a result of screening of over 100 NAs in a real-time HBV-PCR assay, we identified a candidate compound, 4′-cyano-2′deoxyguanosine (CdG, Chart 1), which showed superior antiviral activity against ADV-resistant HBV (HBV A181T/N236T ) and ETV-resistant HBV (HBV L180M/S202G/M204V ) to ADV and ETV, respectively. 4) In addition, a study of the pharmacokinetics of CdG in healthy rats showed that CdG possessed favorable pharmacokinetic properties for use as an oral NA preparation against HBV infections with good bioavailability and a high distribution to the liver.…”
A nucleoside analog, 4′-cyano-2′-deoxyguanosine (CdG), which was developed as an inhibitor of the chronic hepatitis B virus (HBV), exhibited a superior antiviral activity against both wild-type and drugsresistant HBV to marketed nucleoside analogs. In addition to previous pharmacokinetic studies of CdG in healthy rats, this study reports on an evaluation of the pharmacokinetic characteristics of CdG in a rat model of viral liver injury (VLI) induced by treatment with concanavalin A. Following an intravenous administration of CdG at a dose of 1 mg/kg, the plasma concentration profile of CdG in VLI model rats was found to be similar to that of healthy rats with no significant difference in kinetic parameters. However, when CdG was orally administered at a dose of 1 mg/kg, the maximum blood concentration was much lower in VLI model rats than in healthy rats. Interestingly, the amount of residual food in the stomachs in VLI model rats was significantly larger than that in healthy rats, indicating that the adsorption of CdG in the gastrointestinal tract was inhibited in the presence of food as well as other marketed nucleoside analogs. As observed in healthy rats, CdG was largely distributed to the liver compared to the kidney in the VLI model. These results suggest that liver pathology has only a minor effect on the pharmacokinetic properties of CdG, but the influence of food on CdG absorption needs to be considered.
“…The use of substituent that has an ethynyl (−CCH) or cyano (−CN) group added to the ribose ring of an NRTI has been used in compounds other than EFdA (Figure ): a similar approach inspired the design of HBV NRTIs that have a 4′-cyano and are expected to act by a similar mechanism of inhibition (Figure ). , In addition, remdesivir, a related compound with a 1-ethynyl substitution on the ribose ring, has been introduced as a potent RNA-dependent RNA polymerase inhibitor of Ebola and recently approved as the first antiviral against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) (Figure ). − Hence, compounds that act by unique and multiple mechanisms of action may be able to maintain antiviral activity if only a single of their mechanism of action is reversed.…”
Section: Strategies To Avoid Drug Resistancementioning
HIV
reverse transcriptase (RT) is an enzyme that plays a major
role in the replication cycle of HIV and has been a key target of
anti-HIV drug development efforts. Because of the high genetic diversity
of the virus, mutations in RT can impart resistance to various RT
inhibitors. As the prevalence of drug resistance mutations is on the
rise, it is necessary to design strategies that will lead to drugs
less susceptible to resistance. Here we provide an in-depth review
of HIV reverse transcriptase, current RT inhibitors, novel RT inhibitors,
and mechanisms of drug resistance. We also present novel strategies
that can be useful to overcome RT’s ability to escape therapies
through drug resistance. While resistance may not be completely avoidable,
designing drugs based on the strategies and principles discussed in
this review could decrease the prevalence of drug resistance.
Nucleosides and their derivatives are a well-known and well-described class of compounds with antiviral activity. Currently, in the era of the COVID-19 pandemic, scientists are also looking for compounds not related to nucleosides with antiviral properties. This review aims to provide an overview of selected synthetic antiviral agents not associated to nucleosides developed against human viruses and introduced to preclinical and clinical trials as well as drugs approved for antiviral therapy over the last 10 years. The article describes for the first time the wide classification of such antiviral drugs and drug candidates and briefly summarizes the biological target and clinical applications of the compounds. The described compounds are arranged according to the antiviral mechanism of action. Knowledge of the drug's activity toward specific molecular targets may be the key to researching new antiviral compounds and repositioning drugs already approved for clinical use. The paper also briefly discusses the future directions of antiviral therapy. The described examples of antiviral compounds can be helpful for further drug development.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
