Tenofovir diphosphate (PMPApp) is a weak inhibitor of DNA polymerases (pol) alpha, delta, and epsilon*, with values for the Ki for PMPApp ((PMPApp)Ki) relative to the Km for dATP ((dATP)Km) of 10.2, 10.2, and 15.2, respectively. Its incorporation into DNA was about 1,000-fold less efficient than that of dATP, with (PMPApp)Km values 350-, 2,155-, and 187-fold higher than (dATP)Km values for pol alpha, delta, and epsilon*, respectively.

Institute of Organic Chemistry and Biochemistry Academy of Sciences of the Czech Republic

Zobrazit více v PubMed

Balzarini, J., T. Vahlenkamp, H. Eqberink, K. Hartmann, M. Witvrouw, C. Pannecouque, P. Casara, J. F. Nave, and E. De Clercq. 1997. Antiretroviral activities of acyclic nucleoside phosphonates [9-(2-phosphonylmethoxyethyl)-adenine, 9-(2-phosphonylmethoxyethyl)guanine, (R)-9-(2-phosphonylmethoxy-propyl)adenine, and MDL 74,968] in cell cultures and murine sarcoma virus-infected newborn NMRI mice. Antimicrob. Agents Chemother. 41:611-616. PubMed PMC

Balzarini, J., A. Holý, J. Jindřich, L. Naesens, R. Snoeck, D. Schols, and E. De Clercq. 1993. Differential antiherpesvirus and antiretrovirus effects of the (S) and (R) enantiomers of acyclic nucleoside phosphonates: potent and selective in vitro and in vivo antiretrovirus activities of (R)-9-(2-phosphonomethoxypropyl)-2,6-diaminopurine. Antimicrob. Agents Chemother. 37:332-338. PubMed PMC

Barditch-Crovo, P., S. G. Deeks, A. C. Collier, S. Safrin, D. Coakley, M. D. Miller, B. P. Kearney, R. L. Coleman, P. D. Lamy, J. O. Kahn, I. McGowan, and P. S. Lietman. 2001. Phase I/II trial of the pharmacokinetics, safety, and antiretroviral activity of tenofovir disoproxil fumarate in human immunodeficiency virus type 1-infected adults. Antimicrob. Agents Chemother. 45:2733-2739. PubMed PMC

Birkuš, G., J. M. Hitchcock, and T. Cihlar. 2002. Mitochondrial toxicity in human cells treated with tenofovir: comparison with other nucleoside reverse transcriptase inhibitors. Antimicrob. Agents Chemother. 46:716-723. PubMed PMC

Birkuš, G., I. Votruba, B. Otová, M. Otmar, and A. Holý. 1999. HPMPApp as a substrate toward replicative DNA polymerases α, δ and ɛ, p. 289-293. In A. Holý and M. Hocek (ed.), Collection symposium series, vol. 2. Institute of Organic Chemistry and Biochemistry, Academy of Sciences of Czech Republic, Prague.

Birkuš, G., I. Votruba, A. Holý, and B. Otová. 1999. 9-[2-(Phosphonomethoxy)ethyl]adenine (PMEApp) as a substrate toward replicative DNA polymerases α, δ, ɛ and ɛ*. Biochem. Pharmacol. 58:487-492. PubMed

Birkuš, G., P. Kramata, I. Votruba, B. Otová, M. Otmar, and A. Holý. 1998. Nonproteolyzed form of DNA polymerase ɛ from T-cell spontaneous lymphoma of Sprague-Dawley inbred rat: isolation and characterization. Collect. Czech. Chem. Commun. 63:723-731.

Boosalis, M. S., J. Petruska, and M. F. Goodman. 1987. DNA polymerase insertion fidelity. Gel assay for site-specific kinetics. J. Biol. Chem. 262:14689-14696. PubMed

Cherrington, J. M., S. J. W. Allen, N. Bischofberger, and M. S. Chen. 1995. Kinetic interaction of the diphosphates of 9-(2-phosphonylmethoxyethyl)adenine and other anti-HIV active purine congeners with HIV reverse transcriptase and human DNA polymerases α, β, and γ. Antivir. Chem. Chemother. 6:217-221.

Cihlar, T., G. Birkuš, D. E. Greenwalt, and M. J. M. Hitchcock. Tenofovir exhibits low cytotoxicity in various human cell types—comparison with other nucleoside reverse transcriptase inhibitors. Antivir. Res., in press. PubMed

Cihlar, T., E. S. Ho, D. C. Lin, and A. S. Mulato. 2001. Human renal organic anion transporter 1 (hOAT1) and its role in the nephrotoxicity of antiviral nucleotide analogs. Nucleosides Nucleotides Nucleic Acids 20:641-648. PubMed

Cihlar, T., and N. Bischofberger. 1998. PMEA and PMPA: acyclic nucleoside phosphonates with potent anti-HIV activity, p. 105-116. In H. Van der Goot (ed.), Trends in drug research II. Elsevier, Amsterdam, The Netherlands.

Cihlar, T., and M. S. Chen. 1997. Incorporation of selected nucleoside phosphonates and anti-human immunodeficiency virus nucleotide analogues into DNA by human DNA polymerases α, β and γ. Antivir. Chem. Chemother. 8:87-195.

De Clercq, E., T. Sakuma, M. Baba, R. Pauwels, J. Balzarini, I. Rosenberg, and A. Holy. 1987. Antiviral activity of phosphonylmethoxyalkyl derivatives of purine and pyrimidines. Antivir. Res. 8:261-272. PubMed

Fien, K., and B. Stillman. 1992. Identification of replication factor C from Saccharomyces cerevisiae: a component of the leading-strand DNA replication complex. Mol. Cell. Biol. 12:155-163. PubMed PMC

Holý, A., and M. Masojídková. 1995. Synthesis of enantiomeric N-(2-phosphonomethoxypropyl) derivatives of purine and pyrimidine bases. 1. The stepwise approach. Collect. Czech. Chem. Commun. 60:1196-1212.

Holý, A., and I. Rosenberg. 1987. Synthesis of 9-(2-phosphonylmethoxyethyl)-adenine and related compounds. Collect. Czech. Chem. Commun. 52:2801-2809.

James, J. S. 2001. Tenofovir approved: broad indication. AIDS Treat. News 373:2-3. PubMed

Kramata, P., and K. M. Downey. 1999. 9-(2-Phosphonylmethoxyethyl) derivatives of purine nucleotide analogs: a comparison of their metabolism and interaction with cellular DNA synthesis. Mol. Pharmacol. 56:1262-1270. PubMed

Kramata, P., K. M. Downey, and L. R. Paborsky. 1998. Incorporation and excision of 9-(2-phosphonylmethoxyethyl)guanine (PMEG) by DNA polymerase δ and ɛ in vitro. J. Biol. Chem. 273:21966-21971. PubMed

Kramata, P., I. Votruba, B. Otová, and A. Holý. 1996. Different inhibitory potencies of acyclic phosphonomethoxyalkyl nucleotide analogs toward DNA polymerases α, δ and ɛ. Mol. Pharmacol. 49:1005-1011. PubMed

Kramata, P., J. erný, G. Birkuš, I. Votruba, B. Otová, and A. Holý. 1995. DNA polymerases α, δ and ɛ from T-cell spontaneous lymphoblastic leukemia of Sprague-Dawley inbred rat: isolation and characterization. Collect. Czech. Chem. Commun. 60:1555-1572.

Krejèová, R., K. Horská, I. Votruba, and A. Holý. 2000. Phosphorylation of purine (phosphonomethoxy)alkyl derivatives by mitochondrial AMP kinase (AK2 type) from L1210 cells. Collect. Czech. Chem. Commun. 65:1653-1668.

Martin, J. L., C. E. Brown, N. Matthews-Davis, and J. E. Reardon. 1994. Effects of antiviral nucleoside analogs on human DNA polymerases and mitochondrial DNA synthesis. Antimicrob. Agents Chemother. 38:2743-2749. PubMed PMC

Otová, B., A. Holý, I. Votruba, M. Sladká, V. Bílá, B. Mejsnarová, and V. Lešková. 1997. Genotoxicity of purine acyclic nucleotide analogs. Folia Biol. (Prague) 43:225-229. PubMed

Pauwels, R., J. Balzarini, D. Schols, M. Baba, J. Desmyter, L. Rosenberg, A. Holy, and E. De Clercq 1988. Phosphonylmethoxyethyl purine derivatives, a new class of anti-human immunodeficiency virus agents. Antimicrob. Agents Chemother. 32:1025-1030. PubMed PMC

Pisarev, V. M., S. H. Lee, M. C. Connelly, and A. Fridland. 1997. Intracellular metabolism and action of acyclic nucleoside phosphonates on DNA replication. Mol. Pharmacol. 52:63-68. PubMed

Robbins, B. L., J. Greenhaw, M. C. Connelly, and A. Fridland. 1995. Metabolic pathways for activation of the antiviral agent 9-(2-phosphonylmethoxyethyl)adenine in human lymphoid cells. Antimicrob. Agents Chemother. 39:2304-2308. PubMed PMC

Srinivas, R. V., and A. Fridland. 1998. Antiviral activities of 9-R-2-phosphonomethoxypropyl adenine (PMPA) and bis(isopropyloxymethylcarbonyl)PMPA against various drug-resistant human immunodeficiency virus strains. Antimicrob. Agents Chemother. 42:1484-1487. PubMed PMC

Suo, Z., and K. A. Johnson. 1998. Selective inhibition of HIV-1 reverse transcriptase by an antiviral inhibitor, (R)-9-(2-phosphonylmethoxypropyl)adenine. J. Biol. Chem. 273:27250-27258. PubMed

Veselý, J., A. Merta, I. Votruba, I. Rosenberg, and A. Holý. 1990. The cytostatic effects and mechanism of action of antiviral acyclic adenine nucleotide analogs in L1210 mouse leukemia cells. Neoplasma 37:105-110. PubMed