rna polymerase inhibitor

RNA polymerase II-IN-2 (compound 20iii), a potent inhibitor of RNA polymerase II (Pol II) with a K i value of 9.5 nM, demonstrates cytotoxicity against cancer cells, exhibiting toxicity levels 2 and 5 times higher than α-amanitin in CHO and HEK293 cells, respectively [1].

T7 RNA polymerase, expressed by Escherichia coli from the T7 bacteriophage RNA polymerase gene, is a highly specific enzyme utilized for in vitro transcription (IVT) of mRNA. This polymerase requires Mg 2+ and selects only DNA templates that contain the T7 promoter sequence, whether single-stranded or double-stranded. It employs NTPs to synthesize RNA that is complementary to the single-stranded DNA following the promoter [1] [2].

PTBP1-RNA-binding inhibitor P6 (PTBP1 α3-helix derived peptide P6) TFA is a stapled peptide that acts as an inhibitor for the splicing factor PTBP1, targeting the alternative splicing events this protein regulates. It operates by binding to RNA via PTBP1's RNA recognition motif [1].

RNA polymerase II-IN-1 (compound 19iv), an amatoxin, selectively inhibits RNA polymerase II (Pol II) with an IC50 of 36.66 nM. It exhibits heightened cytotoxicity towards cancer cells and reduced toxicity in normal cells compared to α-Amanitin [1].

Favipiravir (T-705) (T-705), an effective and selective RNA-dependent RNA polymerase inhibitor, are applied to treat influenza virus infections.

Filibuvir (PF-00868554) is a selective and noncovalent inhibitor of HCV NS5B RNA-dependent RNA polymerase. Filibuvir inhibits genotype 1a and 1b replicons with EC50s of 59 nM.

JTK-109 is an inhibitor of hepatitis C virus NS5B RNA-dependent RNA polymerase inhibitor and inhibits G1b and G3a subgenomic replicons and recombinant enzymes.

2’-beta-C-Methyl inosine (2’-C-Methylinosine) is an HCV RNA polymerase inhibitor with antiviral activity and is being studied for the treatment of hepatitis C virus infection.

(S)-Enitociclib (VIP152) is a selective CDK9 inhibitor that induces complete regression of MYC+ lymphomas by inhibiting RNA polymerase II-mediated transcription of anti-apoptotic and pro-survival proteins.

Setrobuvir (ANA-598) is an orally active non-nucleoside HCV NS5B polymerase inhibitor with inhibitory effects on de novo RNA synthesis and primer extension with IC50s between 4 and 5 nM. setrobuvir shows good binding affinity for SARS-CoV-2 RdRp and induces inhibition of RdRp.

Talviraline (Bay 10-8979) is an RNA-induced DNA polymerase inhibitor.Talviraline is a potent inhibitor of HIV-1-induced cell killing and HIV-1 replication in a variety of human cell lines, as well as in fresh human peripheral blood lymphocytes and macrophages.

Uprifosbuvir (MK-3682) is a uridine nucleoside monophosphate prodrug inhibitor of hepatitis C virus NS5B RNA polymerase with antiviral activity for the study of chronic hepatitis C virus.

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.

TMC-649128 PM is a potent nucleoside inhibitor of the HCV NS5B RNA-dependent RNA polymerase, displaying an EC(50) value of 1.2 muM and showing moderate in vivo bioavailability in rat (F=14%).

IMT1B (LDC203974) is an orally administered, specific noncompetitive allosteric inhibitor of the mitochondrial RNA polymerase (POLRMT), effectively suppressing mitochondrial DNA (mtDNA) expression. This action confers it with anti-tumor properties.

Sotetsuflavone, with an IC50 of 0.16 μM, stands as the most active compound in its series, acting as a potent inhibitor of DENV-NS5 RdRp (Dengue virus NS5 RNA-dependent RNA polymerase).

BMH-21, a small molecule DNA intercalator, binds ribosomal DNA and inhibits RNA polymerase I (Pol I) transcription and not affects phosphorylation of H2AX.

Fidaxomicin (Tiacumicin B) is a semisynthetic macrolide antibiotic used to treat Clostridium difficile-associated diarrhea in adults. Fidaxomicin has minimal systemic absorption and has not been linked to serum enzyme elevations during therapy or to instances of clinically apparent, acute liver injury.

Cynaroside (Luteolin 7-O-Glucoside) is a flavone, a flavonoid-like chemical compound. It has an anti-oxidant effect, inhibiting lipid and protein oxidation.

Baloxavir (S-033447) is a first-in-class cap-dependent endonuclease inhibitor of the influenza virus polymerase PA subunit.

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

Mal-C6-α-Amanitin, an ADC (antibody-drug conjugate) linker drug, incorporates the powerful antitumor agent α-Amanitin, an inhibitor of RNA polymerase II, through the Mal-C6 linker, showcasing potent antitumor activity.

MC-VC-PABC-C6-alpha-Amanitin is an antibody-drug conjugate that combines the anticancer toxin alpha-Amanitin with the monoclonal antibody MC-VC-PABC-C6. Alpha-Amanitin acts as a potent inhibitor of RNA polymerase IIα, enabling the conjugate to selectively target and recognize HER2-positive tumor cells. This specificity makes MC-VC-PABC-C6-alpha-Amanitin a valuable research tool in the study of breast and gastric cancers [1].

Suramin is a reversible, competitive inhibitor of protein-tyrosine phosphatases (PTPases) [1], demonstrating potent inhibition against sirtuins: SirT1 (IC50=297 nM), SirT2 (IC50=1.15 μM), and SirT5 (IC50=22 μM) [2]. It also acts as a competitive inhibitor of reverse transcriptase (DNA topoisomerase II: IC50=5 μM) [3] [4] and exhibits potent inhibition of SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) [5]. Additionally, Suramin effectively inhibits IP5K, showcasing its antiparasitic, anti-neoplastic, and anti-angiogenic properties [6] [7] [8].

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.

FIT-039 is a selective and ATP-competitive, orally active inhibitor of CDK9( IC50 : 5.8 μM;CDK9/cyclin T1). FIT-039 inhibits replication of HSV-1 (IC50 of 0.69 μM), HSV-2, human adenovirus, and human CMV. FIT-039 is a promising antiviral agent for inhibiting drug-resistant HSVs and other DNA viruses.

7-51A is an effective inhibitor of the PB2 subunit of the influenza RNA-dependent RNA polymerase (RdRP), with a dissociation constant (K_D) of 1.64 nM as determined by isothermal titration calorimetry (ITC).

Streptolydigin inhibits RNA synthesis by binding to RNA polymerase and does not inhibit eukaryotic RNA polymerases. Streptolydigin is a 3-acetyltetramic acid antibiotic and a potent bacterial RNA polymerase inhibitor (Ki: 18 μM and a Kd: 15 μM).

2'-Deoxyadenosine-5'-triphosphate (Deoxyadenosine 5-triphosphate) (dATP) is a naturally occurring small molecule nucleotide used in cells for DNA synthesis or replication. 2'-Deoxyadenosine-5'-triphosphate (dATP) is a substrate for DNA polymerase. 2'-Deoxyadenosine-5'-triphosphate (dATP) is an inhibitor of RNA through an inactive alpha4beta4 quaternary structure. Deoxyadenosine-5'-triphosphate inhibits RNA through the inactive α4beta4 quaternary structure.2'-Deoxyadenosine-5'-triphosphate has been associated with cardiomyocyte growth.

Methyl 2-amino-5-bromobenzoate (Methyl 5-Bromoanthranilate) is a hepatitis C virus NS5b RNA polymerase inhibitor with antimicrobial activity that inhibits Pseudomonas aeruginosa infections and is involved in the production of many virulence factors and biofilm formation.

MC-VC-PABC-DNA31 is a drug-linker conjugate designed for Antibody-Drug Conjugates (ADC) that demonstrates potent antitumor activity. It employs DNA31, an effective inhibitor of RNA polymerase, connected through the MC-VC-PABC ADC linker.

Pseudouridimycin is a C-nucleoside analogue. Pseudouridimycin is an antibiotic and is a selective bacterial RNA polymerase (RNAP) inhibitor. It is effective against both Gram-negative and Gram-positive bacteria.

ZIKV-IN-6 (compound 22) acts as a direct inhibitor of the Zika virus (ZIKV) by binding to its RNA-dependent RNA polymerase (RdRp) and obstructing viral RNA synthesis mediated by the ZIKV NS5 protein. This compound also demonstrates low cytotoxicity (CC50 >50 μM) and mitigates the excessive inflammatory response and pyroptosis [1].

JNJ-8003 is a potent inhibitor of RSV Polymerase, effectively impeding the early stages of RNA transcription and replication by inhibiting nucleotide polymerization [1].

AZD-4573 is a selective and short-acting inhibitor of the serine/threonine cyclin-dependent kinase 9, the catalytic subunit of the RNA polymerase II elongation factor positive transcription elongation factor b. It also has a potential antineoplastic activ

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

Pol I-IN-1 is a powerful inhibitor of RNA polymerase I (Pol I), specifically targeting the large catalytic subunit RPA194, demonstrating an inhibition concentration (IC50) of 0.21 μM [1].

DENV-IN-4 is a potent inhibitor of DENV (DENV EC50=4.79 μM, Vero CC50>100 μM, SI>20.9). The antiviral effect was demonstrated by the concentration-dependent reduction of DENV2 expression and the inhibition of RNA-dependent RNA polymerase (RdRp) activity.

Pidnarulex HCl is the salt form of CX-5461, a first-in-class non-genotoxic small molecule targeted inhibitor of RNA polymerase I (Pol I) that activates the p53 pathway without causing DNA damage. CX-5461 selectively inhibits rRNA synthesis by Pol I in the nucleolus, but does not inhibit mRNA synthesis by RNA Polymerase II (Pol II) and does not inhibit DNA replication or protein synthesis. Inhibition of Pol I results in nucleolar stress and release of ribosomal proteins (RP) from the nucleolus. The RP bind to Mdm2 and liberate p53 to orchestrate apoptosis in cancer cells. CX-5461 demonstrates a favorable preclinical profile, potently and selectively kills cancer cells, demonstrates robust in vivo efficacy in multiple models, and has demonstrated oral bioavailability in multiple species.

Cap-dependent endonuclease-IN-9 is a potent (CEN) inhibitor with notable efficacy against the influenza virus and exhibits minimal cytotoxicity, enhanced in vivo pharmacokinetics, and robust pharmacodynamics. It effectively suppresses the RNA polymerase activity of A virus[1].

YKL-5-124 TFA, a potent and selective irreversible covalent inhibitor of CDK7, demonstrates IC50 values of 53.5 nM for CDK7 and 9.7 nM for the CDK7/Mat1/CycH complex. It exhibits over 100-fold selectivity for CDK7 over CDK9 and CDK2, while showing no activity against CDK12 and CDK13. This compound effectively induces cell-cycle arrest, inhibits E2F-driven gene expression, and has minimal impact on the phosphorylation status of RNA polymerase II.

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.

CYP2C19-IN-1 is a potent, non-genotoxic, non-hepatotoxic inhibitor of CYP2C19. CYP2C19-IN-1 inhibits RNA-dependent RNA polymerase (RdRP) (Ki: 6.16 μM) and can be used to study Zika virus (ZIKV) infection.

MFH290 is a novel cysteine (Cys)-directed covalent inhibitor of CDK12/13. MFH290 forms a covalent bond with Cys-1039 of CDK12, exhibits excellent kinome selectivity, inhibits the phosphorylation of serine-2 in the C-terminal domain (CTD) of RNA-polymerase II (Pol II), and reduces the expression of key DNA damage repair genes. Importantly, these effects were demonstrated to be CDK12-dependent as mutation of Cys-1039 rendered the kinase refractory to MFH290 and restored Pol II CTD phosphorylation and DNA damage repair gene expression. Consistent with its effect on DNA damage repair gene expression, MFH290 augments the antiproliferative effect of the PARP inhibitor olaparib.

Mericitabine (R-7128) is a nucleoside HCV NS5B polymerase inhibitor. It acts as an RNA chain terminator and prevents the elongation of RNA transcripts during replication.

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.

RdRP-IN-7, a RNA-dependent RNA polymerase (RdRp) inhibitor, demonstrates efficacy against SARS-CoV-2 infection with an inhibitory concentration (IC50) of 8.2 μM and (IC90) of 14.1 μM, alongside a cytotoxic concentration (CC90) of 79.1 μM, rendering it suitable for antiviral research [1].

2'-Deoxy-2'-fluoroadenosine-5'-O-triphosphate is a fluorinated analog of ATP, the pivotal energy substrate for cellular metabolism, and acts as an inhibitor of E. coli RNA polymerase (Ki = 200 µM).