23 results on '"Feng, Joy"'
Search Results
2. Effects of HIV Q151M-associated multi-drug resistance mutations on the activities of (−)-β- d-1′,3′-dioxolan guanine
- Author
-
Feng, Joy Y., Myrick, Florence, Selmi, Boulbaba, Deval, Jérôme, Canard, Bruno, and Borroto-Esoda, Katyna
- Published
- 2005
- Full Text
- View/download PDF
3. Dead-end complexes contribute to the synergistic inhibition of HIV-1 RT by the combination of rilpivirine, emtricitabine, and tenofovir
- Author
-
Kulkarni, Rima, Feng, Joy Y., Miller, Michael D., and White, Kirsten L.
- Published
- 2014
- Full Text
- View/download PDF
4. Anabolism of amdoxovir: phosphorylation of dioxolane guanosine and its 5′-phosphates by mammalian phosphotransferases
- Author
-
Feng, Joy Y., Parker, William B., Krajewski, Megan L., Deville-Bonne, Dominique, Veron, Michel, Krishnan, Preethi, Cheng, Yung-Chi, and Borroto-Esoda, Katyna
- Subjects
- *
METABOLISM , *PHOSPHORYLATION , *DIOXOLANES , *GUANOSINE triphosphate , *PHOSPHOTRANSFERASES - Abstract
Amdoxovir [(-)-β-D-2,6-diaminopurine dioxolane, DAPD], the prodrug of dioxolane guanosine (DXG), is currently in Phase I/II clinical development for the treatment of HIV-1 infection. In this study, we examined the phosphorylation pathway of DXG using 15 purified enzymes from human (8), animal (6), and yeast (1) sources, including deoxyguanosine kinase (dGK), deoxycytidine kinase (dCK), high Km 5′-nucleotidase (5′-NT), guanylate (GMP) kinase, nucleoside monophosphate (NMP) kinase, adenylate (AMP) kinase, nucleoside diphosphate (NDP) kinase, 3-phosphoglycerate (3-PG) kinase, creatine kinase, and pyruvate kinase. In addition, the metabolism of 14C-labeled DXG was studied in CEM cells. DXG was not phosphorylated by human dCK, and was a poor substrate for human dGK with a high Km (7mM). Human 5′-NT phosphorylated DXG with relatively high efficiency (4.2% of deoxyguanosine). DXG–MP was a substrate for porcine brain GMP kinase with a substrate specificity that was 1% of dGMP. DXG–DP was phosphorylated by all of the enzymes tested, including NDP kinase, 3-PG kinase, creatine kinase, and pyruvate kinase. The BB-isoform of human creatine kinase showed the highest relative substrate specificity (47% of dGDP) for DXG–DP. In CEM cells incubated with 5μM DXG for 24h, 0.015pmole/106 cells (~7.5nM) of DXG–TP was detected as the primary metabolite. Our study demonstrated that 5′-nucleotidase, GMP kinase, creatine kinase, and NDP kinase could be responsible for the activation of DXG in vivo. [Copyright &y& Elsevier]
- Published
- 2004
- Full Text
- View/download PDF
5. Characterization of Novel Reverse Transcriptase and Other RNA-associated Catalytic Activities by Human DNA Polymerase γ.
- Author
-
Murakami, Eisuke, Feng, Joy Y., Lee, Harold, Hanes, Jeremiah, Johnson, Kenneth A., and Anderson, Karen S.
- Subjects
- *
REVERSE transcriptase , *CATALYTIC RNA , *DNA polymerases - Abstract
Details a study which sought to characterize novel reverse transcriptase and other RNA-associated catalytic activities by human DNA polymerase gamma. Formation of DNA/RNA heteroduplex during mitochondrial DNA replication; Findings that polymerase gamma also incorporates ribonucleotide triphosphate into a DNA primer.
- Published
- 2003
- Full Text
- View/download PDF
6. Dioxolane Guanosine 5′-Triphosphate, an Alternative Substrate Inhibitor of Wild-type and Mutant HIV-1 Reverse Transcriptase.
- Author
-
Jeffrey, Jerry L., Feng, Joy Y., Qi, C.C. Richard, Anderson, Karen S., and Furman, Phillip A.
- Subjects
- *
CHROMOGENIC compounds , *MICROBIAL mutation - Abstract
Investigates the use of dioxolone guanosine 5'-triphosphate (DXG-TP) as an alternative substrate inhibitor of wild-type and mutant HIV-1 reverse transcriptase. Inhibition of HIV-1 Rt by DXG-TP; Retention of dGMP incorporation by DXG-TP; Increase in the level of resistance to inhibition by nucleoside analogs.
- Published
- 2003
- Full Text
- View/download PDF
7. Mechanism and spectrum of inhibition of a 40 -cyano modified nucleotide analog against diverse RNA polymerases of prototypic respiratory RNA viruses.
- Author
-
Gordon, Calvin J., Walker, Simon M., Tchesnokov, Egor P., Kocincova, Dana, Pitts, Jared, Siegel, Dustin S., Perry, Jason K., Feng, Joy Y., Bilello, John P., and Götte, Matthias
- Subjects
- *
RNA polymerases , *PANDEMIC preparedness , *MITOCHONDRIAL RNA , *RESPIRATORY syncytial virus , *RNA viruses - Abstract
The development of safe and effective broad-spectrum antivirals that target the replication machinery of respiratory viruses is of high priority in pandemic preparedness programs. Here, we studied the mechanism of action of a newly discovered nucleotide analog against diverse RNA-dependent RNA polymerases (RdRps) of prototypic respiratory viruses. GS646939 is the active 50 -triphosphate metabolite of a 4ʹ-cyano modified C-adenosine analog phosphoramidate prodrug GS7682. Enzyme kinetics show that the RdRps of human rhinovirus type 16 (HRV-16) and enterovirus 71 incorporate GS646939 with unprecedented selectivity; GS-646939 is incorporated 20-50-fold more efficiently than its natural ATP counterpart. The RdRp complex of respiratory syncytial virus and human metapneumovirus incorporate GS-646939 and ATP with similar efficiency. In contrast, influenza B RdRp shows a clear preference for ATP and human mitochondrial RNA polymerase does not show significant incorporation of GS646939. Once incorporated into the nascent RNA strand, GS646939 acts as a chain terminator although higher NTP concentrations can partially overcome inhibition for some polymerases. Modeling and biochemical data suggest that the 4ʹmodification inhibits RdRp translocation. Comparative studies with GS-443902, the active triphosphate form of the 10 -cyano modified prodrugs remdesivir and obeldesivir, reveal not only different mechanisms of inhibition, but also differences in the spectrum of inhibition of viral polymerases. In conclusion, 1ʹcyano and 4ʹ-cyano modifications of nucleotide analogs provide complementary strategies to target the polymerase of several families of respiratory RNA viruses. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
8. Prevention and therapy of SARS-CoV-2 and the B.1.351 variant in mice.
- Author
-
Martinez, David R., Schäfer, Alexandra, Leist, Sarah R., Li, Dapeng, Gully, Kendra, Yount, Boyd, Feng, Joy Y., Bunyan, Elaine, Porter, Danielle P., Cihlar, Tomas, Montgomery, Stephanie A., Haynes, Barton F., Baric, Ralph S., Nussenzweig, Michel C., and Sheahan, Timothy P.
- Abstract
Improving clinical care for individuals infected with SARS-CoV-2 variants is a global health priority. Small-molecule antivirals like remdesivir (RDV) and biologics such as human monoclonal antibodies (mAbs) have demonstrated therapeutic efficacy against SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19). It is not known whether combination RDV/mAb will improve outcomes over single-agent therapies or whether antibody therapies will remain efficacious against variants. Here, we show that a combination of two mAbs in clinical trials, C144 and C135, have potent antiviral effects against even when initiated 48 h after infection and have therapeutic efficacy in vivo against the B.1.351 variant of concern (VOC). Combining RDV and antibodies provided a modest improvement in outcomes compared with single agents. These data support the continued use of RDV to treat SARS-CoV-2 infections and the continued clinical development of the C144 and C135 antibody combination to treat patients infected with SARS-CoV-2 variants. [Display omitted] • Early treatment with remdesivir or antibodies is most effective against COVID-19 • Remdesivir has therapeutic efficacy against SARS-CoV-2 WA/1 in mice • C144 + C135 mAb therapy is effective against SARS-CoV-2 WA/1 and B.1.351 variant • Remdesivir and mAb combination therapy has a modest improvement in mice Martinez et al. demonstrate that remdesivir and C144 + C135 mAb cocktail can curtail SARS-CoV-2 disease in mice, including against the B.1.351 variant. The combination of remdesivir + mAbs had a modest therapeutic benefit in mice. Early therapy with remdesivir and/or mAbs had the most benefit against COVID-19. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
9. The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus.
- Author
-
Gordon, Calvin J., Tchesnokov, Egor P., Feng, Joy Y., Porter, Danielle P., and Götte, Matthias
- Subjects
- *
MERS coronavirus , *RNA replicase , *MIDDLE East respiratory syndrome , *RNA polymerases , *EXONUCLEASES , *RNA viruses , *REMDESIVIR - Abstract
Antiviral drugs for managing infections with human coronaviruses are not yet approved, posing a serious challenge to current global efforts aimed at containing the outbreak of severe acute respiratory syndrome-coronavirus 2 (CoV-2). Remdesivir (RDV) is an investigational compound with a broad spectrum of antiviral activities against RNA viruses, including severe acute respiratory syndrome-CoV and Middle East respiratory syndrome (MERS-CoV).RDVis a nucleotide analog inhibitor of RNA-dependent RNA polymerases (RdRps). Here, we co-expressed the MERS-CoV nonstructural proteins nsp5, nsp7, nsp8, and nsp12 (RdRp) in insect cells as a part a polyprotein to study the mechanism of inhibition of MERS-CoV RdRp by RDV. We initially demonstrated that nsp8 and nsp12 form an active complex. The triphosphate form of the inhibitor (RDVTP) competes with its natural counterpart ATP. Of note, the selectivity value for RDV-TP obtained here with a steady-state approach suggests that it is more efficiently incorporated than ATP and two other nucleotide analogs. Once incorporated at position i, the inhibitor caused RNA synthesis arrest at position i + 3. Hence, the likely mechanism of action is delayed RNA chain termination. The additional three nucleotides may protect the inhibitor from excision by the viral 3'-5' exonuclease activity. Together, these results help to explain the high potency of RDV against RNA viruses in cell-based assays. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
10. Efficient incorporation and template-dependent polymerase inhibition are major determinants for the broad-spectrum antiviral activity of remdesivir.
- Author
-
Gordon, Calvin J., Lee, Hery W., Tchesnokov, Egor P., Perry, Jason K., Feng, Joy Y., Bilello, John P., Porter, Danielle P., and Götte, Matthias
- Subjects
- *
COVID-19 , *SARS-CoV-2 , *CORONAVIRUS disease treatment , *RNA polymerases , *SARS disease , *RNA replicase , *NEURAMINIDASE - Abstract
Remdesivir (RDV) is a direct-acting antiviral agent that is approved in several countries for the treatment of Coronavirus disease 2019 caused by the severe acute respiratory syndrome coronavirus 2. RDV exhibits broad-spectrum antiviral activity against positive-sense RNA viruses, for example, severe acute respiratory syndrome coronavirus and hepatitis C virus, and nonsegmented negative-sense RNA viruses, for example, Nipah virus, whereas segmented negative-sense RNA viruses such as influenza virus or Crimean-Congo hemorrhagic fever virus are not sensitive to the drug. The reasons for this apparent efficacy pattern are unknown. Here, we expressed and purified representative RNA-dependent RNA polymerases and studied three biochemical parameters that have been associated with the inhibitory effects of RDV-triphosphate (TP): (i) selective incorporation of the nucleotide substrate RDV-TP, (ii) the effect of the incorporated RDV-monophosphate (MP) on primer extension, and (iii) the effect of RDV-MP in the template during incorporation of the complementary UTP. We found a strong correlation between antiviral effects and efficient incorporation of RDV-TP. Inhibition in primer extension reactions was heterogeneous and usually inefficient at higher NTP concentrations. In contrast, template-dependent inhibition of UTP incorporation opposite the embedded RDV-MP was seen with all polymerases. Molecular modeling suggests a steric conflict between the 1'-cyano group of the inhibitor and residues of the structurally conserved RNA-dependent RNA polymerase motif F. We conclude that future efforts in the development of nucleotide analogs with a broader spectrum of antiviral activities should focus on improving rates of incorporation while capitalizing on the inhibitory effects of a bulky 1'-modification. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
11. An atomistic model of the Coronavirus replication-transcription complex as a hexamer assembled around nsp15.
- Author
-
Perry, Jason K., Appleby, Todd C., Bilello, John P., Feng, Joy Y., Schmitz, Uli, and Campbell, Elizabeth A.
- Subjects
- *
ZINC-finger proteins , *VIRAL nonstructural proteins , *COVID-19 , *RNA polymerases , *VIRAL genomes , *PROTEIN structure - Abstract
The SARS-CoV-2 replication-transcription complex is an assembly of nonstructural viral proteins that collectively act to reproduce the viral genome and generate mRNA transcripts. While the structures of the individual proteins involved are known, how they assemble into a functioning superstructure is not. Applying molecular modeling tools, including protein-protein docking, to the available structures of nsp7-nsp16 and the nucleocapsid, we have constructed an atomistic model of how these proteins associate. Our principal finding is that the complex is hexameric, centered on nsp15. The nsp15 hexamer is capped on two faces by trimers of nsp14/nsp16/(nsp10)2, which then recruit six nsp12/nsp7/(nsp8)2 polymerase subunits to the complex. To this, six subunits of nsp13 are arranged around the superstructure, but not evenly distributed. Polymerase subunits that coordinate dimers of nsp13 are capable of binding the nucleocapsid, which positions the 5'- UTR TRS-L RNA over the polymerase active site, a state distinguishing transcription from replication. Analysis of the viral RNA path through the complex indicates the dsRNA that exits the polymerase passes over the nsp14 exonuclease and nsp15 endonuclease sites before being unwound by a convergence of zinc fingers from nsp10 and nsp14. The template strand is then directed away from the complex, while the nascent strand is directed to the sites responsible for mRNA capping. The model presents a cohesive picture of the multiple functions of the coronavirus replication-transcription complex and addresses fundamental questions related to proofreading, template switching, mRNA capping, and the role of the endonuclease. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
12. Template-dependent inhibition of coronavirus RNA-dependent RNA polymerase by remdesivir reveals a second mechanism of action.
- Author
-
Tchesnokov, Egor P., Gordon, Calvin J., Woolner, Emma, Kocinkova, Dana, Perry, Jason K., Feng, Joy Y., Porter, Danielle P., and Götte, Matthias
- Subjects
- *
RNA replicase , *COVID-19 , *REMDESIVIR , *SARS-CoV-2 , *INHIBITION (Chemistry) , *HEPATITIS C - Abstract
Remdesivir (RDV) is a direct-acting antiviral agent that is used to treat patients with severe coronavirus disease 2019 (COVID-19). RDV targets the viral RNA-dependent RNA polymerase (RdRp) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We have previously shown that incorporation of the active triphosphate form of RDV (RDV-TP) at position i causes delayed chain termination at position i + 3. Here we demonstrate that the S861G mutation in RdRp eliminates chain termination, which confirms the existence of a steric clash between Ser-861 and the incorporated RDV-TP. With WT RdRp, increasing concentrations of NTP pools cause a gradual decrease in termination and the resulting read-through increases full-length product formation. Hence, RDV residues could be embedded in copies of the first RNA strand that is later used as a template. We show that the efficiency of incorporation of the complementary UTP opposite template RDV is compromised, providing a second opportunity to inhibit replication. A structural model suggests that RDV, when serving as the template for the incoming UTP, is not properly positioned because of a significant clash with Ala-558. The adjacent Val-557 is in direct contact with the template base, and the V557L mutation is implicated in low-level resistance to RDV. We further show that the V557L mutation in RdRp lowers the nucleotide concentration required to bypass this template-dependent inhibition. The collective data provide strong evidence to show that template-dependent inhibition of SARS-CoV-2 RdRp by RDV is biologically relevant. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
13. Remdesivir is a direct-acting antiviral that inhibits RNAdependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency.
- Author
-
Gordon, Calvin J., Tchesnokov, Egor P., Woolner, Emma, Perry, Jason K., Feng, Joy Y., Porter, Danielle P., and Götte, Matthias
- Subjects
- *
CORONAVIRUSES , *HEPATITIS C virus , *COVID-19 , *MERS coronavirus , *HEPATITIS C , *RNA polymerases , *EBOLA virus , *RNA replicase - Abstract
Effective treatments for coronavirus disease 2019 (COVID- 19) are urgently needed to control this current pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Replication of SARS-CoV-2 depends on the viral RNA-dependent RNA polymerase (RdRp), which is the likely target of the investigational nucleotide analogue remdesivir (RDV). RDV shows broad-spectrum antiviral activity against RNA viruses, and previous studies with RdRps from Ebola virus and Middle East respiratory syndrome coronavirus (MERSCoV) have revealed that delayed chain termination is RDV's plausible mechanism of action. Here, we expressed and purified active SARS-CoV-2 RdRp composed of the nonstructural proteins nsp8 and nsp12. Enzyme kinetics indicated that this RdRp efficiently incorporates the active triphosphate form of RDV (RDV-TP) into RNA. Incorporation of RDV-TP at position i caused termination of RNA synthesis at position i+3. We obtained almost identical results with SARS-CoV, MERS-CoV, and SARS-CoV-2 RdRps. A unique property of RDV-TP is its high selectivity over incorporation of its natural nucleotide counterpart ATP. In this regard, the triphosphate forms of 2'-Cmethylated compounds, including sofosbuvir, approved for the management of hepatitisCvirus infection, and the broad-acting antivirals favipiravir and ribavirin, exhibited significant deficits. Furthermore, we provide evidence for the target specificity of RDV, as RDV-TP was less efficiently incorporated by the distantly related Lassa virus RdRp, and termination ofRNAsynthesis was not observed. These results collectively provide a unifying, refined mechanism of RDV-mediated RNA synthesis inhibition in coronaviruses and define this nucleotide analogue as a direct-acting antiviral. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
14. Discovery of β-d-2′-deoxy-2′-α-fluoro-4′-α-cyano-5-aza-7,9-dideaza adenosine as a potent nucleoside inhibitor of respiratory syncytial virus with excellent selectivity over mitochondrial RNA and DNA polymerases.
- Author
-
Clarke, Michael O., Mackman, Richard, Byun, Daniel, Hui, Hon, Barauskas, Ona, Birkus, Gabriel, Chun, Byoung-Kwon, Doerffler, Edward, Feng, Joy, Karki, Kapil, Lee, Gary, Perron, Michel, Siegel, Dustin, Swaminathan, Swami, and Lee, William
- Subjects
- *
DRUG development , *ADENOSINES , *MITOCHONDRIAL RNA , *DNA polymerases , *RESPIRATORY syncytial virus , *NUCLEOSIDE triphosphatase - Abstract
Novel 4′-substituted β- d -2′-deoxy-2′-α-fluoro (2′d2′F) nucleoside inhibitors of respiratory syncytial virus (RSV) are reported. The introduction of 4′-substitution onto 2′d2′F nucleoside analogs resulted in compounds demonstrating potent cell based RSV inhibition, improved inhibition of the RSV polymerase by the nucleoside triphosphate metabolites, and enhanced selectivity over incorporation by mitochondrial RNA and DNA polymerases. Selectivity over the mitochondrial polymerases was found to be extremely sensitive to the specific 4′-substitution and not readily predictable. Combining the most potent and selective 4′-groups from N -nucleoside analogs onto a 2′d2′F C -nucleoside analog resulted in the identification of β- d -2′-deoxy-2′-α-fluoro-4′-α-cyano-5-aza-7,9-dideaza adenosine as a promising nucleoside lead for RSV. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
15. Synthesis and characterization of 1′-C-cyano-2′-fluoro-2′-C-methyl pyrimidine nucleosides as HCV polymerase inhibitors.
- Author
-
Kirschberg, Thorsten A., Mish, Michael R., Zhang, Lijun, Squires, Neil H., Wang, Ke-Yu, Cho, Aesop, Feng, Joy Y., Fenaux, Martijn, Babusis, Darius, Park, Yeojin, Ray, Adrian S., and Kim, Choung U.
- Subjects
- *
PYRIMIDINE synthesis , *POLYMERASES , *HEPATITIS C virus , *ENZYME inhibitors , *PHOSPHORAMIDATES , *PRODRUGS - Abstract
The first synthesis of 1′- C -CN, 2′-F, 2′- C -Me pyrimidines is described. Anti-HCV activity was assessed and compared to the 1′- C -CN, 2′- C -Me as well as the 2′-F, 2′- C -Me pyrimidines. A phosphoramidate prodrug of the cytidine derivative showed activity in the low micromolar range against HCV replicons. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
16. Preparation and biological evaluation of 1′-cyano-2′-C-methyl pyrimidine nucleosides as HCV NS5B polymerase inhibitors.
- Author
-
Mish, Michael R., Cho, Aesop, Kirschberg, Thorsten, Xu, Jie, Sebastian Zonte, C., Fenaux, Martijn, Park, Yeojin, Babusis, Darius, Feng, Joy Y., Ray, Adrian S., and Kim, Choung U.
- Subjects
- *
PYRIMIDINES , *NUCLEOSIDES , *HEPATITIS C virus , *POLYMERASES , *CHEMICAL inhibitors , *ANTIVIRAL agents - Abstract
Abstract: The first synthesis of 1′-cyano-2′-C-methyl pyrimidine nucleosides is described. Anti-HCV activity of these nucleosides and their nucleotide phosphoramidate prodrugs was assessed and compared to the 1′-unsubstituted counterparts and to the related 1′-cyano-2′-C-methyl C-nucleoside parent of GS-6620. [Copyright &y& Elsevier]
- Published
- 2014
- Full Text
- View/download PDF
17. Evaluation of 2′-α-fluorine modified nucleoside phosphonates as potential inhibitors of HCV polymerase.
- Author
-
Parrish, Jay P., Lee, Sharon K., Boojamra, Constantine G., Hui, Hon, Babusis, Darius, Brown, Brandon, Shih, I-hung, Feng, Joy Y., Ray, Adrian S., and Mackman, Richard L.
- Subjects
- *
FLUORINE , *RIBONUCLEOSIDES , *PHOSPHONATES , *HEPATITIS C virus , *RNA polymerases , *ENZYME inhibitors - Abstract
Abstract: Ribonucleoside phosphonate analogues containing 2′-α-fluoro modifications were synthesized and their potency evaluated against HCV RNA polymerase. The diphosphophosphonate (triphosphate equivalent) adenine and cytidine analogues displayed potent inhibition of the HCV polymerase in the range of 1.9–2.1μM, but only modest cell-based activity in the HCV replicon. Pro-drugs of the parent nucleoside phosphonates improved the cell-based activity. [Copyright &y& Elsevier]
- Published
- 2013
- Full Text
- View/download PDF
18. Bifunctional inhibition of HIV-1 reverse transcriptase: A first step in designing a bifunctional triphosphate
- Author
-
Piao, Dongyuan, Basavapathruni, Aravind, Iyidogan, Pinar, Dai, Guangxiu, Hinz, Wolfgang, Ray, Adrian S., Murakami, Eisuke, Feng, Joy Y., You, Fei, Dutschman, Ginger E., Austin, David J., Parker, Kathlyn A., and Anderson, Karen S.
- Subjects
- *
HIV , *REVERSE transcriptase , *AIDS treatment , *POLYETHYLENE glycol , *NUCLEOSIDES , *CHEMICAL synthesis - Abstract
Abstract: The onset of resistance to approved anti-AIDS drugs by HIV necessitates the search for novel inhibitors of HIV-1 reverse transcriptase (RT). Developing single molecular agents concurrently occupying the nucleoside and nonnucleoside binding sites in RT is an intriguing idea but the proof of concept has so far been elusive. As a first step, we describe molecular modeling to guide focused chemical syntheses of conjugates having nucleoside (d4T) and nonnucleoside (TIBO) moieties tethered by a flexible polyethylene glycol (PEG) linker. A triphosphate of d4T–6PEG–TIBO conjugate was successfully synthesized that is recognized as a substrate by HIV-1 RT and incorporated into a double-stranded DNA. [Copyright &y& Elsevier]
- Published
- 2013
- Full Text
- View/download PDF
19. Synthesis and characterization of 2′-C-Me branched C-nucleosides as HCV polymerase inhibitors
- Author
-
Cho, Aesop, Zhang, Lijun, Xu, Jie, Babusis, Darius, Butler, Thomas, Lee, Rick, Saunders, Oliver L., Wang, Ting, Parrish, Jay, Perry, Jason, Feng, Joy Y., Ray, Adrian S., and Kim, Choung U.
- Subjects
- *
NUCLEOSIDES , *DRUG synthesis , *HEPATITIS C virus , *POLYMERASES , *CHEMICAL inhibitors , *PHARMACOLOGY , *PHARMACOKINETICS - Abstract
Abstract: A series of 2′-C-methyl branched purine and pyrimidine C-nucleosides were prepared. Their anti-HCV activity and pharmacological properties were profiled, and compared with known 2′-C-Me N-nucleoside counterparts. In particular, 2′-C-Me 4-aza-7,9-dideazaadenosine C-nucleoside (2) was found to have potent and selective anti-HCV activity in vitro as well as a favorable pharmacokinetic profile and in vivo potential for enhanced potency over the corresponding N-nucleoside. [Copyright &y& Elsevier]
- Published
- 2012
- Full Text
- View/download PDF
20. Structural Basis for the Role of the K65R Mutation in HIV-1 Reverse Transcriptase Polymerization, Excision Antagonism, and Tenofovir Resistance.
- Author
-
Das, Kalyan, Bandwar, Rajiv P., White, Kirsten L., Feng, Joy Y., Sarafianos, Stefan G., Tuske, Steven, Xiongying Tu, Clark, Jr., Arthur D., Boyer, Paul L., Xiaorong Hou, Gaffney, Barbara L., Jones, Roger A., MilIer, Michael D., Hughes, Stephen H., and Arnold, Eddy
- Subjects
- *
GENETIC mutation , *REVERSE transcriptase , *HIV , *GUANIDINE , *ARGININE , *NUCLEOTIDES , *THYMIDINE - Abstract
K65R is a primary reverse transcriptase (RT) mutation selected in human immunodeficiency virus type 1-infected patients taking antiretroviral regimens containing tenofovir disoproxil fumarate or other nucleoside analog RT drugs. We determined the crystal structures of K65R mutant RT cross-linked to double-stranded DNA and in complexes with tenofovir diphosphate (TFV-DP) or dATP. The crystals permit substitution of TFV-DP with dATP at the dNTP-binding site. The guanidinium planes of the arginines K65R and Arg72 were stacked to form a molecular platform that restricts the conformational adaptability of both of the residues, which explains the negative effects of the K65R mutation on nucleotide incorporation and on excision. Furthermore, the guanidinium planes of K65R and Arg72 were stacked in two different rotameric conformations in TFV-DPand dATP-bound structures that may help explain how K65R RT discriminates the drug from substrates. These K65R-mediated effects on RT structure and function help us to visualize the complex interaction with other key nucleotide RT drug resistance mutations, such as M184V, L74V, and thymidine analog resistance mutations. [ABSTRACT FROM AUTHOR]
- Published
- 2009
- Full Text
- View/download PDF
21. Synthesis and antiviral activity of a series of 1′-substituted 4-aza-7,9-dideazaadenosine C-nucleosides
- Author
-
Cho, Aesop, Saunders, Oliver L., Butler, Thomas, Zhang, Lijun, Xu, Jie, Vela, Jennifer E., Feng, Joy Y., Ray, Adrian S., and Kim, Choung U.
- Subjects
- *
ANTIVIRAL agents , *RNA viruses , *POLYMERASES , *NUCLEOSIDE triphosphatase , *BIOSYNTHESIS , *HEPATITIS C virus , *ENZYME inhibitors - Abstract
Abstract: A series of 1′-substituted analogs of 4-aza-7,9-dideazaadenosine C-nucleoside were prepared and evaluated for the potential as antiviral agents. These compounds showed a broad range of inhibitory activity against various RNA viruses. In particular, the whole cell potency against HCV when R=CN was attributed to inhibition of HCV NS5B polymerase and intracellular concentration of the corresponding nucleoside triphosphate. [Copyright &y& Elsevier]
- Published
- 2012
- Full Text
- View/download PDF
22. Biochemical characterization of tirabrutinib and other irreversible inhibitors of Bruton's tyrosine kinase reveals differences in on - and off - target inhibition.
- Author
-
Liclican, Albert, Serafini, Loredana, Xing, Weimei, Czerwieniec, Gregg, Steiner, Bart, Wang, Ting, Brendza, Katherine M., Lutz, Justin D., Keegan, Kathleen S., Ray, Adrian S., Schultz, Brian E., Sakowicz, Roman, and Feng, Joy Y.
- Subjects
- *
PROTEIN-tyrosine kinases , *CD19 antigen , *SMALL molecules , *KINASES , *B cells - Abstract
Bruton's tyrosine kinase (BTK) is a key component of the B-cell receptor (BCR) pathway and a clinically validated target for small molecule inhibitors such as ibrutinib in the treatment of B-cell malignancies. Tirabrutinib (GS-4059/ONO-4059) is a selective, once daily, oral BTK inhibitor with clinical activity against many relapsed/refractory B-cell malignancies. Covalent binding of tirabrutinib to BTK Cys-481 was assessed by LC-MSMS analysis of BTK using compound as a variable modification search parameter. Inhibition potency of tirabrutinib, ibrutinib, acalabrutinib, and spebrutinib against BTK and related kinases was studied in a dose-dependent manner either after a fixed incubation time (as used in conventional IC 50 studies) or following a time course where inactivation kinetics were measured. Tirabrutinib irreversibly and covalently binds to BTK Cys-481. The inactivation efficiency k inact /K i was measured and used to calculate selectivity among different kinases for each of the four inhibitors studied. Tirabrutinib showed a k inact /K i value of 2.4 ± 0.6 × 104 M−1 s−1 for BTK with selectivity against important off-targets. For the BTK inhibitors tested in this study, analysis of the inactivation kinetics yielded a more accurate measurement of potency and selectivity than conventional single-time point inhibition measurements. Subtle but clear differences were identified between clinically tested BTK inhibitors which may translate into differentiated clinical efficacy and safety. This is the first study that offers a detailed side-by-side comparison of four clinically-relevant BTK inhibitors with respect to their inactivation of BTK and related kinases. • The inactivation kinetics of four clinically-relevant BTK inhibitors on BTK and related kinases are characterized. • Kinetics were measured for tirabrutinib, ibrutinib, acalabrutinib, and spebrutinib. • Selectivity between kinases was determined based on the inactivation kinetics. • Tirabrutinib irreversibly and covalently binds to the Cys-481 residue of BTK and is a potent and selective BTK inhibitor. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
23. Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic deltacoronaviruses with a highly divergent RNA dependent RNA polymerase.
- Author
-
Brown, Ariane J., Won, John J., Graham, Rachel L., Dinnon III, Kenneth H., Sims, Amy C., Feng, Joy Y., Cihlar, Tomas, Denison, Mark R., Baric, Ralph S., and Sheahan, Timothy P.
- Subjects
- *
RNA polymerases , *RNA , *INFECTIOUS disease transmission , *ANIMALS , *PARAMYXOVIRUSES , *ZOONOSES , *REMDESIVIR , *CORONAVIRUSES - Abstract
The genetically diverse Orthocoronavirinae (CoV) family is prone to cross species transmission and disease emergence in both humans and livestock. Viruses similar to known epidemic strains circulating in wild and domestic animals further increase the probability of emergence in the future. Currently, there are no approved therapeutics for any human CoV presenting a clear unmet medical need. Remdesivir (RDV, GS-5734) is a monophosphoramidate prodrug of an adenosine analog with potent activity against an array of RNA virus families including Filoviridae , Paramyxoviridae , Pneumoviridae , and Orthocoronavirinae , through the targeting of the viral RNA dependent RNA polymerase (RdRp). We developed multiple assays to further define the breadth of RDV antiviral activity against the CoV family. Here, we show potent antiviral activity of RDV against endemic human CoVs OC43 (HCoV-OC43) and 229E (HCoV-229E) with submicromolar EC 50 values. Of known CoVs, the members of the deltacoronavirus genus have the most divergent RdRp as compared to SARS- and MERS-CoV and both avian and porcine members harbor a native residue in the RdRp that confers resistance in beta-CoVs. Nevertheless, RDV is highly efficacious against porcine deltacoronavirus (PDCoV). These data further extend the known breadth and antiviral activity of RDV to include both contemporary human and highly divergent zoonotic CoV and potentially enhance our ability to fight future emerging CoV. • In vitro antiviral assays were developed for human CoV OC43 and 229E and the zoonotic PDCoV. • The nucleoside analog RDV inhibited HCoV-OC43 and 229E as well as deltacoronavirus member PDCoV. • RDV has broad-spectrum antiviral activity against CoV and should be evaluated for future emerging CoV. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.