termination

Carboprost (15(S)-15-Methyl Prostaglandin F2α) is a synthetic analogue of PGF2α with oxytocic properties, commonly used to restore uterine tone.

GJ071 oxalate is a Nonsense suppressor. Nonsense suppressors (NonSups) induce readthrough , i.e., the selection of near cognate tRNAs at premature termination codons and insertion of the corresponding amino acid into nascent polypeptide.

Patamostat mesylate (E-3123) is a potent protease inhibitor with IC50 values of 39 nM for trypsin, 950 nM for plasmin, and 1.9 μM for thrombin. This compound demonstrates promising potential in suppressing the pathogenesis and development of acute pancreatitis.

Paromomycin binds specifically to the RNA oligonucleotide at the A site of bacterial 30S ribosomes, thereby causing misreading and premature termination of translation of mRNA and inhibition of protein synthesis followed by cell death. Paromomycin Sulfate (Aminosidine sulfate) is the sulfate salt form of paromomycin, a structural derivative of neomycin, an aminoglycoside antibiotic with amebicidal and bactericidal effects against predominantly aerobic gram-negative bacteria.

BSJ-4-116 is a highly potent and selective CDK12 degrader (PROTAC) with an IC50 of 6 nM. It downregulates DDR genes through a premature termination of transcription, primarily through increasing poly(adenylation).

beta-L-D4A, a nucleoside HIV-1 reverse transcriptase inhibitor, exhibits biological activity by terminating DNA chain synthesis in the 5'-3' direction.

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.

ALS-8112 (ALS 008112) is a selective and potent inhibitor of respiratory syncytial virus (RSV) polymerase with an IC50 value of 0.02 μM. ALS-8112 exhibits antiviral activity and inhibits the RNA polymerase activity of the RSV L-P protein complex through RNA chain termination. virus infections.

Gemcitabine elaidate (CP-4126), is a lipophilic, unsaturated fatty acid ester derivative of gemcitabine (dFdC), an antimetabolite deoxynucleoside analogue, with potential antineoplastic activity. Upon hydrolysis intracellularly by esterases, the prodrug gemcitabine is converted into the active metabolites difluorodeoxycytidine di- and tri-phosphate (dFdCDP and dFdCTP) by deoxycytidine kinase. dFdCDP inhibits ribonucleotide reductase, thereby decreasing the deoxynucleotide pool available for DNA synthesis; dFdCTP is incorporated into DNA, resulting in DNA strand termination and apoptosis.

Cymipristone, a progesterone receptor antagonist, is used potentially for termination of intrauterine pregnancy.

GJ-072 is a Nonsense suppressor. Nonsense suppressors (NonSups) induce readthrough , i.e., the selection of near cognate tRNAs at premature termination codons and insertion of the corresponding amino acid into nascent polypeptide.

RTC14, as a premature termination codon (PTC) readthrough inducer, can act by restoring dystrophin expression and improving muscle function in the mdx mouse model for Duchenne muscular dystrophy.

Insulin-degrading enzyme (IDE) is a thiol-sensitive zinc-metallopeptidase that acts as the major insulin-degrading protease in vivo, mediating the termination of insulin signaling. [1] In addition to regulating insulin action in diabetes pathogenesis, IDE plays a role in Varicella-Zoster virus infection and degradation of amyloid-β, a peptide implicated in Alzheimer's disease. ML-345 is a small molecule inhibitor that selectively targets cysteine819 in IDE with an EC50 value of 188 nM. [2] It demonstrates 10-fold selectivity for IDE over a panel of enzymes with reactive cysteine residues.[2] Reference:[1]. Maianti, J.P., McFedries, A., Foda, Z.H., et al. Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones. Nature 511(7507), 94-98 (2014).[2]. Bannister, T.D., Wang, H., Abdul-Hay, S.O., et al. ML345, a small-molecule inhibitor of the insulin-degrading enzyme (IDE). 1 R03 DA024888-01 (MLSCN cycle 6), 1-41 (2014).

9-deoxy-9-methylene-16,16-dimethyl Prostaglandin E2 (Meteneprost) is a potent analog of prostaglandin E2 with an extended half-life in vivo. In combination with various other prostaglandin derivatives, it results in the termination of first trimester pregnancy in monkeys. A single intramuscular injection containing 0.5 mg of meteneprost and 7.5 mg of 17-phenyl trinor PGF1α is very effective in terminating early pregnancy. This prostaglandin mixture is ineffective on monkeys in their third trimester of pregnancy. Meteneprost, when compared to PGE2 and PGF1α, in monkey and rat, does not result in unwanted side effects such as fever or gastrointestinal problems.

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.

Novel oxylipins, referred to as docosanoids, have been derived from C22polyunsaturated fatty acids 7(S),17(S)-dihydroxy-8(E),10(Z),13(Z),15(E),19(Z)-Docosapentaenoic acid (7(S),17(S)-hydroxy DPA) is a DPA-derived analog of the 17(S)-dihydroxy series of docosanoids known as protectins. Protectin D1, a DHA-derived dihydroxy fatty acid, exhibits potent anti-inflammatory activities.1,2,3Potentially, 7(S),17(S)-hydroxy DPA demonstrates similar properties; however, its biological activity has yet to be determined. 1.Serhan, C.N., Gotlinger, K., Hong, S., et al.Anti-inflammatory actions of neuroprotectin D1/protectin D1 and its natural stereoisomers: Assignments of dihydroxy-containing docosatrienesJ. Immunol.176(3)1848-1859(2006) 2.Ariel, A., and Serhan, C.N.Resolvins and protectins in the termination program of acute inflammationTRENDS in Immunology28(4)176-183(2007) 3.Schwab, J.M., Chiang, N., Arita, M., et al.Resolvin E1 and protectin D1 activate inflammation-resolution programmesNature447(7146)869-874(2007)

Ensartinib (X-396) is a potent and orally active dual ALK MET inhibitor for the treatment of ALK-positive non-small cell lung cancer (NSCLC).

KCa2 (small conductance Ca2+-activated potassium) channel negative allosteric modulator (IC50 = 1.1 μM). Increases the EC50 of Ca2+ on KCa2.3 channels by ~3-fold. Prolongs atrial effective refractory period (AERP) in rats. Reduces atrial fibrillation (AF) duration and prolongs atrial refractoriness without affecting ventricular refractory period in an animal AF model. Diness et al (2017) Termination of vernakalant-resistant atrial fibrillation by inhibition of small-conductance Ca2+-activated K+ channels in pigs. Circ.Arrhythm.Electrophysiol. 10 e005125 PMID:29018164 |Simó-Vicens et al (2017) A new negative allosteric modulator, AP14145, for the study of small conductance calcium-activated potassium (KCa2) channels. Br.J.Pharmacol. 174 4396 PMID:28925012

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)

EFdA-TP, a highly potent nucleoside reverse transcriptase (RT) inhibitor, exerts its inhibitory effect on RT-catalyzed DNA synthesis through both immediate and delayed chain termination mechanisms, commonly referred to as ICT and DCT, respectively. Additionally, EFdA-TP demonstrates its efficacy in inhibiting HIV-1 RT through multiple pathways.

Tezacitabine is a cytostatic and cytotoxic antimetabolite and a nucleoside analogue with a dual mechanism of action that irreversibly inhibits ribonucleotide reductase and can be incorporated into DNA during replication or repair, causing DNA chain termination. It blocks tumor cells in the G1 and S phases of the cell cycle, inducing apoptotic cell death, with potential applications in treating leukemia and solid tumors[1][2].

SRI-41315 is an eRF1 degrader that acts as a molecular glue at the center of ribosomal decoding.SRI-41315 induces an extended pause at the termination codon and inhibits cystic fibrosis-associated PTC in immortalized and primary human bronchial epithelial cells, restoring CFTR expression and function.SRI-41315 inhibits PTC by decreasing the abundance of the termination factor eRF1 NIOCH 14

SRI-37240 is a potent inhibitor of premature termination codons (PTCs) with read-across activity that induces a prolonged pause at the termination codon and inhibits PTCs associated with cystic fibrosis.SRI-37240 can be used to study PTC-related diseases.

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.