viral polymerase

Viral polymerase-IN-1 hydrochloride, a derivative of Gemcitabine, effectively inhibits influenza A and B virus infections with IC90 values between 11.4 and 15.9 μM, and shows activity against SARS-CoV-2 infection by interfering with viral RNA replication transcription within cells [1].

Foscarnet sodium (Phosphonoformate) is an antiviral agent used in the treatment of cytomegalovirus retinitis. Foscarnet also shows activity against human herpesviruses and HIV.

Penciclovir (BRL 39123) is a Herpesvirus Nucleoside Analog DNA Polymerase Inhibitor. In HSV infected cells, penciclovir is phosphorylated by viral thymidine kinase and subsequently converted by cellular kinases into the active metabolite, penciclovir triphosphate, which competitively inhibits viral HSV polymerase by blocking deoxyguanosine triphosphate substrate binding. As a result, herpes viral DNA synthesis and replication are selectively inhibited.

Valganciclovir hydrochloride (Valganciclovir HCl) is a hydrochloride salt form of valganciclovir, a prodrug form of ganciclovir, a nucleoside analog of 2'-deoxyguanosine, with antiviral activity. After phosphorylation, valganciclovir is incorporated into DNA, resulting in inhibition of viral DNA polymerase, and viral replication.

GS-6620 PM is a derivative of GS-6620, an orally administered anti-hepatitis C virus polymerase inhibitor and a novel potent C-nucleoside adenine analogue monophosphate prodrug.GS-6620 has limited activity against other viruses and maintains only partial activity against the closely related bovine viral diarrhea virus (EC50, 1.5 μM).

PP7 is a potent inhibitor of PB1-PB2 interaction(IC50 of 8.6 μM).

Galidesivir hydrochloride is an inhibitor of viral RNA-dependent RNA polymerase (RdRp). It inhibits SARS-CoV-2 by tightly binding to its RdRp.

Galidesivir is a viral RNA-dependent RNA polymerase (RdRP) inhibitor and broad spectrum antiviral nucleotide.In vitro, galidesivir displays antiviral activity against a range of RNA viruses, including bunyaviruses, arenaviruses, paramyxoviruses, coronaviruses, and flaviviruses (EC50values range from 3 μM to >100 μM). Galidesivir protects against Ebola and Marburg viral infection in animal models.

AS-136A is an orally active measles virus RNA-dependent RNA polymerase (RdRp) inhibitor with antiviral activity that inhibits measles virus and blocks viral RNA synthesis.

Galidesivir (BCX4430) is a broad-spectrum antiviral compound, an adenosine analog that inhibits viral RNA-dependent RNA polymerase (RdRp) activity.Galidesivir inhibits a wide range of RNA viral pathogens in vitro, and reduces lung infections in infected animals.

Dasabuvir (ABT-333) is a non-nucleoside inhibitor of the hepatitis C virus (HCV) non-structural protein 5B (NS5B), an RNA-dependent RNA polymerase. Upon administration and intracellular uptake, dasabuvir binds HCV NS5B polymerase, blocking viral RNA synthesis and replication. The HCV NS5B protein is essential for the replication of the HCV RNA genome.

NITD-2 is a dengue virus (DENV) polymerase inhibitor, inhibits the DENV RdRp-mediated RNA elongation. NITD-2 penetrates cell membrane poorly. Dengue virus (DENV) is the most prevalent mosquito- borne viral pathogen in humans. Neither vaccine nor antiviral therapy is currently available for DENV.

Clevudine (Levovir) is a synthetic pyrimidine analogue with activity against hepatitis B virus (HBV). Intracellularly, clevudine is phosphorylated to its active metabolites, clevudine monophosphate and triphosphate. The triphosphate metabolite competes with thymidine for incorporation into viral DNA, thereby causing DNA chain termination and inhibiting the function of HBV DNA polymerase (reverse transcriptase). Clevudine has a long half-life and shows significant reduction of covalently closed circular DNA (cccDNA), therefore the patient is less likely to have a relapse after treatment is discontinued.

Cidofovir dihydrate (HPMPC) is an anti-CMV drug, It can suppress CMV replication by selective inhibition of viral DNA polymerase and therefore prevention of viral replication and transcription. Cidofovir dihydrate is an injectable antiviral medication primarily used as a treatment for cytomegalovirus (CMV) retinitis- an infection of the retina of the eye in people with AIDS

Dexelvucitabine (RVT), a nucleoside reverse transcriptase inhibitor, is used potentially for the treatment of HIV infection.

Pimodivir, also known as VX-787, JNJ-872, is a novel inhibitor of influenza virus replication that blocks the PB2 cap-snatching activity of the influenza viral polymerase complex. VX-787 binds the cap-binding domain of the PB2 subunit with a KD (dissociation constant) of 24 nM as determined by isothermal titration calorimetry (ITC). The cell-based EC50 (the concentration of compound that ensures 50% cell viability of an uninfected control) for VX-787 is 1.6 nM in a cytopathic effect (CPE) assay, with a similar EC50 in a viral RNA replication assay. VX-787 is active against a diverse panel of influenza A virus strains, including H1N1pdm09 and H5N1 strains, as well as strains with reduced susceptibility to neuraminidase inhibitors (NAIs).

Favipiravir sodium is a selective inhibitor of viral RNA-dependent RNA polymerase with activity against many RNA viruses, influenza viruses, West Nile virus, yellow fever virus, foot-and-mouth disease virus as well as other flaviviruses, arenaviruses, bunyaviruses and alphaviruses.

HCVP-IN-1 (compound 1) is an inhibitor of hepatitis C viral polymerase (HCVP).

NHC-triphosphate tetrasodium, the active phosphorylated intracellular metabolite of β-d-N4-Hydroxycytidine (NHC) in its triphosphate form, functions as a weak alternative substrate for viral polymerase, allowing its incorporation into HCV replicon RNA.

BVDU 5′-Triphosphate is an antiviral agent labeled with 5′-Triphosphate that specifically targets viral DNA polymerase. It exhibits outstanding selectivity for varicella-zoster virus (VZV) and herpes simplex virus type 1 (HSV-1) owing to its phosphorylation by the virus-specific thymidine kinase.

NHC-triphosphate triammonium is an active phosphorylated intracellular metabolite of β-d-N4-Hydroxycytidine (NHC) as a triphosphate form[1]. NHC-triphosphate triammonium is a weak alternative substrate for the viral polymerase and can be incorporated into HCV replicon RNA[1][2]. In an intracellular metabolism assay, HCV replicon cells are treated with 10 μM 3H-labeled NHC, and intracellular nucleotide levels are determined after 1, 2 and 8 hours incubations. NHC is rapidly convered into the mono-, di-, and triphosphate forms, and NHC-TP reaches up to 71.12 pM after 8 hours[1].NHC-triphosphate triammonium (NHC-TP) (5-40 μM) absence leads to full-length polymerization products, it can be a weak alternative substrate. In addition, incorporation of NHC-TP instead of CTP increases the molecular weight of the polymerization product by 16 (one extra oxygen) for each event and an obvious electrophoretic shift is observed in cell-free HCV NS5B polymerization reactions[1].Huh-7 cells are incubated with (10-50 μM; 4 h) NHC or a McGuigan phosphoramidate prodrug of NHC. Intracellular levels of the parental compounds and phosphorylated metabolites are measured using LC-MS/MS. Small amounts of NHC-monophosphate (MP) and NHC-diphosphate (DP) can be observed, while NHC-triphosphate triammonium remains the most abundant metabolite[2].NHC-triphosphate triammonium (NHC-TP) metabolite may directly target the viral polymerase and behave as a nonobligate chain terminator. It plays a prominent role in inhibiting early negative-strand RNA synthesis, either through chain termination or mutagenesis, which may in turn interfere with correct replicase complex formation. [1]. Stuyver LJ,et al. Ribonucleoside analogue that blocks replication of bovine viral diarrhea and hepatitis C viruses in culture.Antimicrob Agents Chemother. 2003 Jan;47(1):244-54. [2]. Maryam Ehteshami, et al. Characterization of β-d- N4-Hydroxycytidine as a Novel Inhibitor of Chikungunya Virus.

Aranotin is a fungal toxin isolated from Arachniotus aureus with activity against RNA viruses such as poliovirus, coxsackie virus, and rhino- and parainfluenza viruses. Aranotin inhibits viral RNA synthesis by impeding the activity of RNA-dependent RNA polymerase.

Acyclovir monophosphate is a potent anti-Herpes Simplex Virus (HSV) agent with antitumor activity, blocking DNA synthesis by inhibiting viral DNA polymerase and terminating viral DNA chain elongation [1] [2].

Lobucavir inhibits the replication of the HIV virus in T cells, monocytes & macrophages in vitro by inhibiting DNA polymerase and viral DNA synthesis.

RSV L-protein-IN-5 (Compound E) serves as a potent inhibitor of the Respiratory Syncytial Virus (RSV), with an EC50 value of 0.1 μM. It targets RSV polymerase with an IC50 of 0.66 μM and impedes RSV mRNA synthesis through the inhibition of transcript guanylation. The compound demonstrates moderate cytotoxicity, with a CC50 of 10.7 μM in HEp-2 cells, and effectively reduces viral titers in mouse models of RSV infection [1].

Azvudine hydrochloride (RO-0622) is a potent nucleoside reverse transcriptase inhibitor (NRTI) with strong antiviral effects against HIV, HBV, and HCV. It demonstrates highly potent inhibition of HIV-1 (EC50 ranging from 0.03 to 6.92 nM) and HIV-2 (EC50 ranging from 0.018 to 0.025 nM), and effectively inhibits NRTI-resistant viral strains.

2'-Deoxy-2'-fluoro-l-uridine, an L-nucleoside compound, is a potent and selective inhibitor of viral RNA polymerase, effectively inhibiting RNA virus replication [1].

Galidesivir triphosphate is a substrate for viral RNA-dependent RNA polymerase (RDRP), resulting in termination of viral RNA replication and thus serves as an antiviral. Galidesivir triphosphate inhibits HCV NS5B RNA polymerase activity and protects mice against Ebola. Galidesivir triphosphate (Immucillin-A triphosphate) is converted by the prodrug Galidesivir.

Pimodivir is an inhibitor of influenza virus replication that blocks the PB2 cap-snatching activity of the influenza viral polymerase complex. The cell-based EC50 for VX-787 is 1.6 nM in a cytopathic effect (CPE) assay. VX-787 is active against a diverse

Cidofovir diphosphate triethylamine, an active intracellular metabolite of Cidofovir, acts as a selective inhibitor of viral DNA polymerases. It exhibits inhibitory constants (K_i) of 6.6 μM for human cytomegalovirus (HCMV) DNA polymerase, 0.86 μM for herpes simplex virus-1 (HSV-1) DNA polymerase, and 1.4 μM for herpes simplex virus-2 (HSV-2) DNA polymerase, demonstrating its efficacy against these viral enzymes [1] [2].

Fosfonet sodium is a sodium salt formulation of phosphonoacetic acid with activity against herpes simplex viruses and other members of the herpes virus family. Fosfonet inhibits viral DNA polymerase and inhibits the synthesis of viral DNA.

GS-441524 is a potent inhibitor of feline infectious peritonitis (FIP) virus with an EC50 of 0.78 μM.. GS-441524 strongly inhibits feline infectious peritonitis (FIP) virus in tissue culture and experimental cat infection studies. GS-441524 is a molecular precursor to a pharmacologically active nucleoside triphosphate molecule. These analogs act as an alternative substrate and RNA-chain terminator of viral RNA dependent RNA polymerase. GS-441524 was non-toxic in feline cells at concentrations as high as 100 uM and effectively inhibited FIPV replication in cultured CRFK cells and in naturally infected feline peritoneal macrophages at concentrations as low as 1 uM. Note: GS-441524 is an active metabolite of Remdesivir.

Idoxuridine hydrate (5-Iodo-2′-deoxyuridine, 5-IUdR, IdUrd) is a competitive inhibitor of phosphorylases. As an iodinated thymidine analogue, it effectively inhibits DNA polymerase and hinders viral replication, making it useful in the treatment of viral eye infections such as herpes simplex keratitis. Against feline herpesvirus, Idoxuridine has been found to have an IC50 value of 4.3 μM [1].

Ribavirin-13C5is intended for use as an internal standard for the quantification of ribavirin by GC- or LC-MS. Ribavirin is an antiviral guanosine nucleoside analog.1,2Upon entry into cells, ribavirin is metabolized to an active triphosphate form that induces viral RNA chain termination and inhibits viral polymerases. It reduces replication in a panel of seven RNA and four DNA viruses in Vero cells (EC50s = 2-95 μg/ml).3Ribavirin also reduces replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Vero cells (EC50= 109.5 μM).4Aerosol administration of ribavirin (30 mg/kg) reduces mortality in a mouse model of influenza A infection.5Formulations containing ribavirin have been used in the treatment of respiratory syncytial virus (RSV), hepatitis C virus (HCV), and viral hemorrhagic fevers. 1.Gilbert, B.E., and Knight, V.Biochemistry and clinical applications of ribavirinAntimicrob. Agents Chemother.30(2)201-205(1986) 2.Gordon, C.J., Tchesnokov, E.P., Woolner, E., et al.Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potencyJ. Biol. Chem.295(20)6785-6797(2020) 3.Kirsi, J.J., North, J.A., McKernan, P.A., et al.Broad-spectrum antiviral activity of 2-β-D-ribofuranosylselenazole-4-carboxamide, a new antiviral agentAntimicrob. Agents Chemother.24(3)353-361(1983) 4.Wang, M., Cao, R., Zhang, L., et al.Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitroCell Res.30(3)269-271(2020) 5.Wilson, S.Z., Knight, V., Wyde, P.R., et al.Amantadine and ribavirin aerosol treatment of influenza A and B infection in miceAntimicrob. Agents Chemother.17(4)642-648(1980)

ZIKV-IN-6 (compound 22) is a direct inhibitor of the Zika virus (ZIKV) that binds to its RNA-dependent RNA polymerase (RdRp), obstructing viral RNA synthesis mediated by the ZIKV NS5 protein. The compound exhibits low cytotoxicity (CC50 >50 μM) and mitigates excessive inflammatory response and pyroptosis [1].

Oosporein is a mycotoxin produced by Trichoderma reesei with antimicrobial, antiviral and insecticidal activities, inhibits P. infestans, inhibits herpes simplex virus type 1 DNA polymerase, and can be used in the study of viral infections.

NHC-triphosphate is a weak alternative substrate for the viral polymerase and changes the mobility of the product in polyacrylamide electrophoresis gels.

Ribavirin (Tribavirin) is a synthetic nucleoside analog of ribofuranose with activity against hepatitis C virus and other RNA viruses.