Phylogenetic Analysis and Emerging Drug Resistance against Different Nucleoside Analogues in Hepatitis B Virus Positive Patients
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ABSTRACT:
SUBMITTER: Gohar M
PROVIDER: S-EPMC10673510 | biostudies-literature | 2023 Oct
REPOSITORIES: biostudies-literature
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Project description:Fleximers, a novel type of flexible nucleoside that have garnered attention due to their unprecedented activity against human coronaviruses, have now exhibited highly promising levels of activity against filoviruses. The Flex-nucleoside was the most potent against recombinant Ebola virus in Huh7 cells with an EC50=2μM, while the McGuigan prodrug was most active against Sudan virus-infected HeLa cells with an EC50 of 7μM.
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Project description:BackgroundNorovirus (NoV) is the leading cause of epidemic gastroenteritis worldwide. The lack of a cell culture has significantly hampered the development of effective therapies against human NoV. Clinically approved nucleoside and non-nucleoside analogues have been used successfully against RNA viruses.MethodsIn this study, we evaluated the efficacy of four nucleoside analogues (2'-C-MeC, 2'-F-2'-C-MeC, β-D-N(4)-hydroxycytidine [NHC] and lamivudine) on Norwalk virus (NV) RNA levels and protein expression in NV replicon-harbouring cells (HG23 cells), and their efficacy in blocking murine norovirus (MNV) replication in RAW 264.7 cells.Results2'-C-MeC and 2'-F-2'-C-MeC reduced MNV RNA levels and infectivity in RAW 264.7 cells in a concentration- and time-dependent manner. The median effective concentrations (EC(50)) of 2'-C-MeC and 2'-F-2'-C-MeC were 6.9 μM and 12.7 μM, respectively. 2'-C-MeC, 2'-F-2'-C-MeC and NHC reduced NV RNA levels and protein expression in HG23 cells. For the NV replicon, the EC(50) of 2'-C-MeC (1.3 μM) was comparable to the antiviral activity of NHC (1.5 μM) and twofold more potent than 2'-F-2'-C-MeC (3.2 μM). The combination of 2'-C-MeC/ribavirin resulted in modest synergistic activity, whereas NHC/ribavirin was antagonistic for NV replication in HG23 cells.ConclusionsThe antiviral activity of 2'-C-MeC against strains of two different NoV genogroups and the low EC(50) suggest that this nucleoside analogue may be effective against the more prevalent GII NoVs. In the absence of a vaccine, antiviral agents could be an effective intervention to control the spread of human NoV in populations at a high risk for NoV disease.
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Project description:A series of tritylated and dimethoxytritylated analogues of selected pyrimidine and purine nucleosides were synthesized and evaluated for their in vitro inhibitory activity against two important members of the genus Flavivirus in the Flaviviridae family, the yellow fever (YFV) and dengue viruses (DENV). Among all compounds tested, the 5'-O-tritylated and the 5'-O-dimethoxytritylated 5-fluorouridine derivatives exerted potency against YFV. Interestingly in the series of purine analogues, the 5'O, N-bis-tritylated fludarabine derivative revealed strong inhibitory activity against DENV at μm concentrations, however significantly weaker potency against YFV.
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Project description:Chronic hepatitis B virus (HBV) infection is a major public health problem that affects millions of people worldwide. Nucleoside analogue reverse transcriptase (RT) inhibitors, such as entecavir (ETV) and lamivudine (3TC), serve as crucial anti-HBV drugs. However, structural studies of HBV RT have been hampered due to its unexpectedly poor solubility. Here, we show that human immunodeficiency virus type-1 (HIV-1) with HBV-associated amino acid substitutions Y115F/F116Y/Q151M in its RT (HIVY115F/F116Y/Q151M) is highly susceptible to ETV and 3TC. Additionally, we experimentally simulated previously reported ETV/3TC resistance for HBV using HIVY115F/F116Y/Q151M with F160M/M184V (L180M/M204V in HBV RT) substituted. We determined crystal structures for HIV-1 RTY115F/F116Y/Q151M:DNA complexed with 3TC-triphosphate (3TC-TP)/ETV-triphosphate (ETV-TP)/dCTP/dGTP. These structures revealed an atypically tight binding conformation of 3TC-TP, where the Met184 side-chain is pushed away by the oxathiolane of 3TC-TP and exocyclic methylene of ETV-TP. Structural analysis of RTY115F/F116Y/Q151M/F160M/M184V:DNA:3TC-TP also demonstrated that the loosely bound 3TC-TP is misaligned at the active site to prevent a steric clash with the side chain γ-methyl of Val184. These findings shed light on the common structural mechanism of HBV and HIV-1 resistance to 3TC and ETV and should aid in the design of new agents to overcome drug resistance to 3TC and ETV.
| S-EPMC7033138 | biostudies-literature
Project description:Chutes and Ladders is an exciting up-and-down-again game in which players race to be the first to the top of the board. Along the way, they will find ladders to help them advance, and chutes that will cause them to move backwards. The development of nucleoside analogs for clinical treatment of hepatitis C presents a similar scenario in which taking shortcuts may help quickly advance a program, but there is always a tremendous risk of being sent backwards as one competes for the finish line. In recent years the treatment options for chronic hepatitis C virus (HCV) infection have expand due to the development of a replicon based in vitro evaluation system, allowing for the identification of multiple drugable viral targets along with a concerted and substantial drug discovery effort. Three major drug targets have reached clinical study for chronic HCV infection: the NS3/4A serine protease, the large phosphoprotein NS5A, and the NS5B RNA-dependent RNA polymerase. Recently, two oral HCV protease inhibitors were approved by the FDA and were the first direct acting anti-HCV agents to result from the substantial research in this area. There are currently many new chemical entities from several different target classes that are being evaluated worldwide in clinical trials for their effectiveness at achieving a sustained virologic response (SVR) (Pham et al., 2004; Radkowski et al., 2005). Clearly the goal is to develop therapies leading to a cure that are safe, widely accessible and available, and effective against all HCV genotypes (GT), and all stages of the disease. Nucleoside analogs that target the HCV NS5B polymerase that have reached human clinical trials is the focus of this review as they have demonstrated significant advantages in the clinic with broader activity against the various HCV GT and a higher barrier to the development of resistant viruses when compared to all other classes of HCV inhibitors.
| S-EPMC3910353 | biostudies-other
Project description:Biochemical response is an important prognostic indicator in chronic hepatitis B (CHB) patients receiving nucleotide/nucleoside analogues (NAs). However, the effects of air pollution in alanine aminotransferase (ALT) normalization remain elusive. This longitudinal study recruited 80 hepatitis B e antigen-negative CHB patients who received NAs. ALT levels were measured during the first year of anti-hepatitis B virus therapy. Normal ALT levels were defined as <19 U/L for females and <30 U/L for males, and the risk factors associated with ALT abnormalities were analyzed. The daily estimations of air pollutants (particulate matter ≤2.5 µm in diameter (PM2.5), nitrogen dioxide, ozone (O3), and benzene) were aggregated into the mean estimation for the previous month based on the date of recruitment (baseline) and 1 year later. Sixteen patients (20.0%) had a baseline ALT > 40 U/L; overall, 41 (51.6%) had an abnormal ALT (≥19 U/L for females and ≥ 30 U/L for males). After 1 year of NA therapy, 75 patients (93.8%) had undetectable hepatitis B virus DNA levels. Mean post-treatment ALT levels were significantly lower than mean pretreatment levels (21.3 vs 30.0 U/L, respectively; P < .001). The proportion of patients with a normal ALT was also significantly higher after versus before treatment (71.2% vs 51.2%, respectively; P = .001). The strongest factors associated with ALT abnormality after 1 year of NA treatment were body mass index (odds ratio [OR], 1.28; 95% confidence interval [CI], 1.05-1.54; P = .01) and ozone level (OR, 1.11; 95% CI, 1.02-1.22; P = .02). Among hepatitis B e antigen-negative CHB patients with relatively low viral loads, 1 year of NA treatment improved ALT levels after the adjustment for confounding factors and increased the proportion of patients with normal ALT levels. Air pollution affects the efficacy of ALT normalization.
| S-EPMC10615411 | biostudies-literature
Project description:8-amino-adenosine (8-NH2-Ado) inhibits RNA synthesis and specifically inhibits synthesis of mRNAs with short half-lives. We hypothesize that the mRNAs affected code for proteins important in apoptosis and glucose metabolism. Gene Expression Arrays will help us understand which gene families may be affected by this drug and give us a better understanding of mechanism of action of this drug 1. MM.1S cells treated with 8-amino-adenosine for 0, 5 hrs and 17 hrs. (myeloma cells sensitive to the drug) 2. U266 cells treated with 8-amino-adenosine for 0, 5 hrs and 17 hrs. (myeloma cells resistant to the drug). 3. Jeko cells treated with 8-amino-adenosine for 0, 5 hrs and 17 hrs. (Mantle cell lymphoma cells sensitive to drug) 4. Granta cells treated with 8-amino-adenosine for 0, 5 hrs and 17 hrs. (Mantle cell lymphoma cells resistant to drug).
2012-05-31 | E-GEOD-38145 | biostudies-arrayexpress
Project description:Multidrug resistance protein 7 (MRP7; ABCC10) is an ATP-binding cassette transporter which is able to transport amphipathic anions and confer resistance to docetaxel and, to a lesser extent, vincristine and paclitaxel. Whereas some detail on the resistance profile of MRP7 is known, the activities of the pump have not been completely determined. Here, it is shown by the analysis of MRP7-transfected HEK293 cells that, in addition to natural product agents, MRP7 is also able to confer resistance to nucleoside-based agents, such as the anticancer agents cytarabine (Ara-C) and gemcitabine, and the antiviral agents 2',3'-dideoxycytidine and PMEA. Consistent with the operation of an efflux pump, expression of MRP7 reduced the accumulation of Ara-C and PMEA. In addition, MRP7 is also able to confer resistance to the microtubule-stabilizing agent epothilone B. Ectopic expression of MRP7 in mouse embryo fibroblasts deficient in P-glycoprotein and Mrp1 revealed that MRP7 has a broad resistance profile for natural product agents. In this drug-sensitive cellular background, MRP7 conferred high levels of resistance to docetaxel (46-fold), paclitaxel (116-fold), SN-38 (65-fold), daunorubicin (7.5-fold), etoposide (11-fold), and vincristine (56-fold). Buthionine sulfoximine did not attenuate MRP7-conferred resistance to docetaxel or Ara-C. These experiments indicate that the resistance capabilities of MRP7 include nucleoside-based agents and a range of natural product anticancer agents that includes nontaxane antimicrotubule agents that are not susceptible to P-glycoprotein-mediated transport and that, unlike MRP1 and MRP2, MRP7-mediated drug transport does not involve glutathione.
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Project description:Metal ions are essential for DNA polymerase and RNase H activities of HIV-1 reverse transcriptase (RT). RT studies are routinely performed at 6-8 mM Mg2+, despite the fact that the in vivo concentration might be as low as 0.2 mM. We studied the influence of MgCl2 and ATP, which likely binds a significant fraction of the magnesium pool in vivo, on the DNA polymerase and RNase H activities of HIV-1 RT, its inhibition by nucleoside RT inhibitors (NRTIs) and primer unblocking by AZT-resistant RT. At low Mg2+ concentration, reverse transcription of a natural template strongly increased despite a dramatically reduced intrinsic polymerase activity under such conditions. Low Mg2+ concentrations affected the RNA stability and indirectly decreased its degradation by the RNase H activity. The reduced RNA degradation prevented premature dissociation of the template and primer strands that otherwise generated dead-end DNA products. In addition, low Mg2+ dramatically decreased the incorporation of NRTIs into DNA and increased nucleotide excision by AZT-resistant RT. The latter effect is also most likely owing to the diminished cleavage of the RNA template. Thus, differences in the free Mg2+ concentration between different cell types or during the cell cycle might strongly affect HIV-1 replication and its inhibition.
| S-EPMC1325016 | biostudies-literature
Project description:8-amino-adenosine (8-NH2-Ado) inhibits RNA synthesis and specifically inhibits synthesis of mRNAs with short half-lives. We hypothesize that the mRNAs affected code for proteins important in apoptosis and glucose metabolism. Gene Expression Arrays will help us understand which gene families may be affected by this drug and give us a better understanding of mechanism of action of this drug
2012-06-01 | GSE38145 | GEO