Tomas Cihlar

Summary

Affiliation: Gilead Sciences
Country: USA

Publications

  1. pmc Histone deacetylase inhibitor romidepsin induces HIV expression in CD4 T cells from patients on suppressive antiretroviral therapy at concentrations achieved by clinical dosing
    Datsen George Wei
    Gilead Sciences, Foster City, California, United States of America
    PLoS Pathog 10:e1004071. 2014
  2. doi request reprint Nucleoside and nucleotide HIV reverse transcriptase inhibitors: 25 years after zidovudine
    Tomas Cihlar
    Department of Biology, Gilead Sciences, Inc, 362 Lakeside Drive, Foster City, CA 94404, USA
    Antiviral Res 85:39-58. 2010
  3. pmc Novel nucleotide human immunodeficiency virus reverse transcriptase inhibitor GS-9148 with a low nephrotoxic potential: characterization of renal transport and accumulation
    Tomas Cihlar
    Gilead Sciences, Inc, Foster City, California 94404, USA
    Antimicrob Agents Chemother 53:150-6. 2009
  4. pmc Design and profiling of GS-9148, a novel nucleotide analog active against nucleoside-resistant variants of human immunodeficiency virus type 1, and its orally bioavailable phosphonoamidate prodrug, GS-9131
    Tomas Cihlar
    Gilead Sciences, 333 Lakeside Dr, Foster City, CA 94404, USA
    Antimicrob Agents Chemother 52:655-65. 2008
  5. ncbi request reprint Molecular assessment of the potential for renal drug interactions between tenofovir and HIV protease inhibitors
    Tomas Cihlar
    Gilead Sciences, Foster City, CA, USA
    Antivir Ther 12:267-72. 2007
  6. ncbi request reprint Discovery of GS-9131: Design, synthesis and optimization of amidate prodrugs of the novel nucleoside phosphonate HIV reverse transcriptase (RT) inhibitor GS-9148
    Richard L Mackman
    Department of Medicinal Chemistry, Gilead Sciences, 333 Lakeside Drive, Foster City, CA94404, USA
    Bioorg Med Chem 18:3606-17. 2010
  7. ncbi request reprint Activation of 9-[(R)-2-[[(S)-[[(S)-1-(Isopropoxycarbonyl)ethyl]amino] phenoxyphosphinyl]-methoxy]propyl]adenine (GS-7340) and other tenofovir phosphonoamidate prodrugs by human proteases
    Gabriel Birkus
    Gilead Sciences, Inc, 362 Lakeside Drive, Foster City, CA 94404, USA
    Mol Pharmacol 74:92-100. 2008
  8. doi request reprint Synthesis and anti-HIV activity of GS-9148 (2'-Fd4AP), a novel nucleoside phosphonate HIV reverse transcriptase inhibitor
    Constantine G Boojamra
    Gilead Sciences, Inc, 333 Lakeside Drive, Foster City, CA 94404, USA
    Bioorg Med Chem Lett 18:1120-3. 2008
  9. ncbi request reprint Synthesis and anti-HIV activity of 2'-fluorine modified nucleoside phosphonates: analogs of GS-9148
    Richard L Mackman
    Gilead Sciences, Inc, 333 Lakeside Drive, Foster City, CA 94404, USA
    Bioorg Med Chem Lett 18:1116-9. 2008
  10. ncbi request reprint Synthesis and anti-HIV activity of cyclic pyrimidine phosphonomethoxy nucleosides and their prodrugs: a comparison of phosphonates and corresponding nucleosides
    Richard L Mackman
    Gilead Sciences, Inc, Foster City, California 94404, USA
    Nucleosides Nucleotides Nucleic Acids 26:573-7. 2007

Collaborators

Detail Information

Publications37

  1. pmc Histone deacetylase inhibitor romidepsin induces HIV expression in CD4 T cells from patients on suppressive antiretroviral therapy at concentrations achieved by clinical dosing
    Datsen George Wei
    Gilead Sciences, Foster City, California, United States of America
    PLoS Pathog 10:e1004071. 2014
    ..In conclusion, RMD induces HIV expression ex vivo at concentrations that can be achieved clinically, indicating that the drug may reactivate latent HIV in patients on suppressive cART. ..
  2. doi request reprint Nucleoside and nucleotide HIV reverse transcriptase inhibitors: 25 years after zidovudine
    Tomas Cihlar
    Department of Biology, Gilead Sciences, Inc, 362 Lakeside Drive, Foster City, CA 94404, USA
    Antiviral Res 85:39-58. 2010
    ..This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, volume 85, issue 1, 2010...
  3. pmc Novel nucleotide human immunodeficiency virus reverse transcriptase inhibitor GS-9148 with a low nephrotoxic potential: characterization of renal transport and accumulation
    Tomas Cihlar
    Gilead Sciences, Inc, Foster City, California 94404, USA
    Antimicrob Agents Chemother 53:150-6. 2009
    ..Compared to acyclic nucleotide analogs, GS-9148 was also found to have lower net active tubular secretion in dogs. Collectively, these results suggest that GS-9148 exhibits a low potential for renal accumulation and nephrotoxicity...
  4. pmc Design and profiling of GS-9148, a novel nucleotide analog active against nucleoside-resistant variants of human immunodeficiency virus type 1, and its orally bioavailable phosphonoamidate prodrug, GS-9131
    Tomas Cihlar
    Gilead Sciences, 333 Lakeside Dr, Foster City, CA 94404, USA
    Antimicrob Agents Chemother 52:655-65. 2008
    ..This favorable preclinical profile makes GS-9131 an attractive clinical development candidate for the treatment of patients infected with NRTI-resistant HIV...
  5. ncbi request reprint Molecular assessment of the potential for renal drug interactions between tenofovir and HIV protease inhibitors
    Tomas Cihlar
    Gilead Sciences, Foster City, CA, USA
    Antivir Ther 12:267-72. 2007
    ....
  6. ncbi request reprint Discovery of GS-9131: Design, synthesis and optimization of amidate prodrugs of the novel nucleoside phosphonate HIV reverse transcriptase (RT) inhibitor GS-9148
    Richard L Mackman
    Department of Medicinal Chemistry, Gilead Sciences, 333 Lakeside Drive, Foster City, CA94404, USA
    Bioorg Med Chem 18:3606-17. 2010
    ..Following oral dosing (3mg/kg) in Beagle dogs, high levels (>9.0microM) of active metabolite 15 were observed in PBMCs, validating the prodrug design process and leading to the nomination of 5 as a clinical candidate...
  7. ncbi request reprint Activation of 9-[(R)-2-[[(S)-[[(S)-1-(Isopropoxycarbonyl)ethyl]amino] phenoxyphosphinyl]-methoxy]propyl]adenine (GS-7340) and other tenofovir phosphonoamidate prodrugs by human proteases
    Gabriel Birkus
    Gilead Sciences, Inc, 362 Lakeside Drive, Foster City, CA 94404, USA
    Mol Pharmacol 74:92-100. 2008
    ....
  8. doi request reprint Synthesis and anti-HIV activity of GS-9148 (2'-Fd4AP), a novel nucleoside phosphonate HIV reverse transcriptase inhibitor
    Constantine G Boojamra
    Gilead Sciences, Inc, 333 Lakeside Drive, Foster City, CA 94404, USA
    Bioorg Med Chem Lett 18:1120-3. 2008
    ....
  9. ncbi request reprint Synthesis and anti-HIV activity of 2'-fluorine modified nucleoside phosphonates: analogs of GS-9148
    Richard L Mackman
    Gilead Sciences, Inc, 333 Lakeside Drive, Foster City, CA 94404, USA
    Bioorg Med Chem Lett 18:1116-9. 2008
    ..The antiviral activity of guanosine analog (2'-Fd4GP) was comparable that of to 2'-Fd4AP in MT-2 cells, but selectivity was reduced...
  10. ncbi request reprint Synthesis and anti-HIV activity of cyclic pyrimidine phosphonomethoxy nucleosides and their prodrugs: a comparison of phosphonates and corresponding nucleosides
    Richard L Mackman
    Gilead Sciences, Inc, Foster City, California 94404, USA
    Nucleosides Nucleotides Nucleic Acids 26:573-7. 2007
    ..Bis-isopropyloxymethylcarbonyl (BisPOC) prodrugs were prepared on selected compounds and provided > 150-fold improvements in antiviral activity...
  11. ncbi request reprint Synthesis, anti-HIV activity, and resistance profiles of ribose modified nucleoside phosphonates
    Richard L Mackman
    Gilead Sciences, Inc, 333 Lakeside Drive, Foster City, CA 94404, USA
    Bioorg Med Chem Lett 17:6785-9. 2007
    ..1 microM, and the most favorable resistance profile against HIV-1 variants with K65R, M184V or multiple thymidine analog mutations in RT...
  12. pmc Intracellular metabolism of the nucleotide prodrug GS-9131, a potent anti-human immunodeficiency virus agent
    Adrian S Ray
    Department of Drug Metabolism, Gilead Sciences, Inc, 333 Lakeside Dr, Foster City, CA 94404, USA
    Antimicrob Agents Chemother 52:648-54. 2008
    ..Together, these observations elucidate the cellular pharmacology of GS-9131 and illustrate its efficient loading of lymphoid cells, resulting in a prolonged intracellular exposure to the active metabolite GS-9148-DP...
  13. doi request reprint Design, synthesis, and anti-HIV activity of 4'-modified carbocyclic nucleoside phosphonate reverse transcriptase inhibitors
    Constantine G Boojamra
    Gilead Science, Inc, Foster City, CA 94404, USA
    Bioorg Med Chem 17:1739-46. 2009
    ..In vitro cellular metabolism studies using 9 confirmed that the active diphosphate metabolite is produced albeit at a lower efficiency relative to GS-9148...
  14. pmc Small molecules VP-14637 and JNJ-2408068 inhibit respiratory syncytial virus fusion by similar mechanisms
    Janet L Douglas
    Gilead, 333 Lakeside Dr, Foster City, CA 94404, USA
    Antimicrob Agents Chemother 49:2460-6. 2005
    ..Altogether, these data indicate that VP-14637 and JNJ-2408068 interfere with RSV fusion through a mechanism involving a similar interaction with the F protein...
  15. ncbi request reprint Tenofovir exhibits low cytotoxicity in various human cell types: comparison with other nucleoside reverse transcriptase inhibitors
    Tomas Cihlar
    Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA
    Antiviral Res 54:37-45. 2002
    ..In conclusion, tenofovir exhibited weak cytotoxic effects in all cell types tested with less in vitro cytotoxicity than the majority of NRTIs currently used for the treatment of HIV disease...
  16. pmc Mechanism of active renal tubular efflux of tenofovir
    Adrian S Ray
    Department of Drug Metabolism, Gilead Sciences, Inc, Foster City, CA 94404, USA
    Antimicrob Agents Chemother 50:3297-304. 2006
    ..A detailed understanding of the molecular mechanism of TFV active tubular secretion will facilitate the assessment of potential renal drug-drug interactions with coadministered agents...
  17. ncbi request reprint Synthesis, anti-HIV activity, and resistance profile of thymidine phosphonomethoxy nucleosides and their bis-isopropyloxymethylcarbonyl (bisPOC) prodrugs
    Richard L Mackman
    Gilead Sciences, Inc, 333 Lakeside Drive, Foster City, CA 94404, USA
    Bioorg Med Chem 15:5519-28. 2007
    ....
  18. pmc Selective intracellular activation of a novel prodrug of the human immunodeficiency virus reverse transcriptase inhibitor tenofovir leads to preferential distribution and accumulation in lymphatic tissue
    William A Lee
    Gilead Sciences, Inc, 333 Lakeside Dr, Foster City, CA 94404, USA
    Antimicrob Agents Chemother 49:1898-906. 2005
    ..2 microg-eq/ml in plasma. A radiolabeled distribution study with dogs resulted in an increased distribution of tenofovir to tissues of lymphatic origin compared to the commercially available prodrug tenofovir DF (Viread)...
  19. ncbi request reprint Mutations in adenosine deaminase-like (ADAL) protein confer resistance to the antiproliferative agents N6-cyclopropyl-PMEDAP and GS-9219
    Christian R Frey
    Biology Department, Gilead Sciences, Inc, 362 Lakeside Dr, Foster City, CA 94404, USA
    Anticancer Res 33:1899-912. 2013
    ..This study investigates the role of adenosine deaminase-like (ADAL) protein in the intracellular activation of GS-9219...
  20. pmc Evaluation of the effect of cobicistat on the in vitro renal transport and cytotoxicity potential of tenofovir
    Kirsten M Stray
    Gilead Sciences, Inc, Foster City, California, USA
    Antimicrob Agents Chemother 57:4982-9. 2013
    ..These results illustrate that COBI and TFV interact primarily with distinct renal transporters and indicate a low potential for pharmacokinetic renal drug-drug interaction. ..
  21. ncbi request reprint Suppression of HIV-1 protease inhibitor resistance by phosphonate-mediated solvent anchoring
    Tomas Cihlar
    Gilead Sciences, Inc, 333 Lakeside Drive, Foster City, CA 94404, USA
    J Mol Biol 363:635-47. 2006
    ..This strategy, which is applicable to various PI scaffolds, should facilitate the design of novel PIs and potentially other antiviral therapeutics...
  22. doi request reprint Visualizing the molecular interactions of a nucleotide analog, GS-9148, with HIV-1 reverse transcriptase-DNA complex
    Eric B Lansdon
    Gilead Sciences, Inc, 333 Lakeside Drive, Foster City, CA 94404, USA
    J Mol Biol 397:967-78. 2010
    ..Interestingly, the 2'-fluoro moiety of GS-9148-diphosphate was found in close proximity to the Q151 side chain, potentially explaining the observed moderately reduced susceptibly to GS-9148 conferred by Q151M mutation...
  23. ncbi request reprint GS-9219--a novel acyclic nucleotide analogue with potent antineoplastic activity in dogs with spontaneous non-Hodgkin's lymphoma
    Hans Reiser
    Department of Research and Development, Gilead Sciences, Inc, Foster City, California 94404, USA
    Clin Cancer Res 14:2824-32. 2008
    ..Our objective was to characterize the antiproliferative activity, pharmacokinetics, pharmacodynamics, and safety of GS-9219...
  24. pmc In vitro characterization of GS-8374, a novel phosphonate-containing inhibitor of HIV-1 protease with a favorable resistance profile
    Christian Callebaut
    Gilead Sciences, 333 Lakeside Dr, Foster City, CA 94404, USA
    Antimicrob Agents Chemother 55:1366-76. 2011
    ....
  25. pmc Role of cathepsin A and lysosomes in the intracellular activation of novel antipapillomavirus agent GS-9191
    Gabriel Birkus
    Biology Department, Gilead Sciences, Inc, 333 Lakeside Drive, Foster City, CA 94404, USA
    Antimicrob Agents Chemother 55:2166-73. 2011
    ....
  26. pmc Cathepsin A is the major hydrolase catalyzing the intracellular hydrolysis of the antiretroviral nucleotide phosphonoamidate prodrugs GS-7340 and GS-9131
    Gabriel Birkus
    Gilead Sciences, Inc, 333 Lakeside Drive, Foster City, CA 94404, USA
    Antimicrob Agents Chemother 51:543-50. 2007
    ..Collectively, these data demonstrate the key role of CatA in the intracellular activation of nucleotide phosphonoamidate prodrugs and open new possibilities for further improvement of this important class of antiviral prodrugs...
  27. pmc Contribution of the organic anion transporter OAT2 to the renal active tubular secretion of creatinine and mechanism for serum creatinine elevations caused by cobicistat
    Eve Irene Lepist
    Gilead Sciences, Foster City, California, USA
    Kidney Int 86:350-7. 2014
    ..Thus, the clinical observation of elevated serum creatinine in patients taking cobicistat is likely a result of OCT2 transport, facilitating intracellular accumulation, and MATE1 inhibition. ..
  28. pmc Mutations in multiple domains of Gag drive the emergence of in vitro resistance to the phosphonate-containing HIV-1 protease inhibitor GS-8374
    Kirsten M Stray
    Gilead Sciences, Inc, Foster City, California, USA
    J Virol 87:454-63. 2013
    ..These substrate changes were distributed throughout Gag and acted in an additive manner. Thus, they are classified as primary resistance mutations indicating a unique mechanism and pathway of resistance development for GS-8374...
  29. doi request reprint Novel targets for HIV therapy
    Warner C Greene
    Gladstone Institute of Virology and Immunology, San Francisco, CA, USA
    Antiviral Res 80:251-65. 2008
    ....
  30. pmc Assessment of mitochondrial toxicity in human cells treated with tenofovir: comparison with other nucleoside reverse transcriptase inhibitors
    Gabriel Birkus
    Gilead Sciences, Foster City, California 94404, USA
    Antimicrob Agents Chemother 46:716-23. 2002
    ..2 microM) and to achieve therapeutically relevant levels in plasma (maximum concentrations in plasma, 0.8 to 1.3 microM) is not associated with mitochondrial toxicity...
  31. pmc Multiple classes of antiviral agents exhibit in vitro activity against human rhinovirus type C
    Chris Mello
    Gilead Sciences, Foster City, California, USA
    Antimicrob Agents Chemother 58:1546-55. 2014
    ....
  32. pmc Inhibition of respiratory syncytial virus fusion by the small molecule VP-14637 via specific interactions with F protein
    Janet L Douglas
    Gilead, Foster City, California 94404, USA
    J Virol 77:5054-64. 2003
    ..Therefore, we propose that VP-14637 inhibits RSV through a novel mechanism involving an interaction between the compound and a transient conformation of the RSV F protein...
  33. pmc Chronic administration of tenofovir to rhesus macaques from infancy through adulthood and pregnancy: summary of pharmacokinetics and biological and virological effects
    Koen K A Van Rompay
    California National Primate Research Center, University of California, Davis, California 95616, USA
    Antimicrob Agents Chemother 52:3144-60. 2008
    ..In conclusion, these findings illustrate the safety and sustained benefits of prolonged TFV-containing regimens throughout development from infancy to adulthood, including pregnancy...
  34. ncbi request reprint Inhibition of the human organic anion transporter 1 by the caffeine metabolite 1-methylxanthine
    Jens Rengelshausen
    Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, D 69120 Heidelberg, Germany
    Biochem Biophys Res Commun 320:90-4. 2004
    ..The central involvement of hOAT1 in the renal excretion of numerous drugs suggests that this inhibition may alter the pharmacokinetics of a series of clinically important drugs in humans...
  35. pmc In vitro cytotoxicity and mitochondrial toxicity of tenofovir alone and in combination with other antiretrovirals in human renal proximal tubule cells
    Francesc Vidal
    Infectious Diseases and AIDS Section, Department of Internal Medicine, Hospital Universitari de Tarragona Joan XXIII, Universitat Rovira i Virgili, Mallafre Guasch, 4, 43007 Tarragona, Spain
    Antimicrob Agents Chemother 50:3824-32. 2006
    ..Together, these in vitro results indicate that combination with other antiretrovirals does not significantly increase the toxic potential of TFV in RPTECs...
  36. ncbi request reprint Unlikely association of multidrug-resistance protein 2 single-nucleotide polymorphisms with tenofovir-induced renal adverse events
    Adrian S Ray
    J Infect Dis 195:1389-90; author reply 1390-1. 2007
  37. ncbi request reprint The anti-influenza drug oseltamivir exhibits low potential to induce pharmacokinetic drug interactions via renal secretion-correlation of in vivo and in vitro studies
    George Hill
    Roche Pharmaceutical Global Development, 3401 Hillview Avenue, Palo Alto, CA 94304, USA
    Drug Metab Dispos 30:13-9. 2002
    ..The study results demonstrate that oseltamivir has a low drug-drug interaction potential at the renal tubular level due to inhibition of hOAT1...