9-(2-Phosphonomethoxyethyl)adenine (PMEA) is an acyclic adenine nucleotide analog which exhibits potent and selective antiviral activity against herpesviruses and retroviruses. The study of [14C]PMEA uptake in HeLa S3 cells has shown that intracellular levels of the drug plateau after 1 h. Transport across the plasma membrane is saturable (concentration at half-maximal saturation [Kt], 0.39 microM; maximum rate of uptake [Vmax], 1.72 pmol/min.10(6) cells), and it can operate against the concentration gradient. Its significant dependence on temperature and on cellular density has been demonstrated. Following the treatment of cells with proteases, PMEA uptake strongly decreases. The transport process is considerably specific, since only a few phosphonate analogs act effectively as competitive inhibitors. Of these, 9-(2-phosphonomethoxyethyl)-2,6-diaminopurine (Ki = 0.24 microM) is the most efficient. Also, natural nucleotides competitively inhibit PMEA transport, depending on the nature of the nucleobase (thymine = adenine > guanine > cytosine < uracil) and on the position and number of phosphate groups. Nucleosides and nucleobases do not interfere with PMEA uptake. Cellular transport of adenosine and thymidine or uptake of AMP and ATP via conjugated activity of ectonucleotidases and nucleoside transporters is not affected by PMEA. By using vectorial labeling of plasma membrane proteins with Na125I combined with affinity chromatography, a 50-kDa protein which may mediate cellular transport of PMEA has been identified.

Institute of Organic Chemistry and Biochemistry Academy of Sciences of The Czech Republic Prague

Zobrazit více v PubMed

Biochemistry. 1988 Oct 4;27(20):7853-8 PubMed

Biochim Biophys Acta. 1988 Oct 11;947(3):405-43 PubMed

Antimicrob Agents Chemother. 1988 Dec;32(12):1839-44 PubMed

Antimicrob Agents Chemother. 1989 Feb;33(2):185-91 PubMed

Proc Natl Acad Sci U S A. 1989 May;86(10):3474-8 PubMed

Methods Enzymol. 1989;173:714-32 PubMed

Eur J Clin Microbiol Infect Dis. 1989 Dec;8(12):1043-7 PubMed

In Vitro Cell Dev Biol. 1990 May;26(5):537-42 PubMed

Antiviral Res. 1990 May;13(5):253-64 PubMed

Antiviral Res. 1990 Jun;13(6):287-93 PubMed

J Biol Chem. 1991 Jan 5;266(1):238-44 PubMed

Antimicrob Agents Chemother. 1988 Jul;32(7):1025-30 PubMed

Antiviral Res. 1991 Jul;16(1):115-9 PubMed

Antiviral Res. 1991 Jul;16(1):93-100 PubMed

Mol Pharmacol. 1992 Sep;42(3):537-44 PubMed

Biochem Pharmacol. 1992 Nov 17;44(10):2067-77 PubMed

Acta Virol. 1992 May;36(3):313-9 PubMed

J Biol Chem. 1993 Mar 5;268(7):5293-301 PubMed

Antimicrob Agents Chemother. 1993 Feb;37(2):332-8 PubMed

Biochem Biophys Res Commun. 1993 Mar 31;191(3):1152-7 PubMed

J Biol Chem. 1993 Jul 25;268(21):15399-404 PubMed

Folia Biol (Praha). 1993;39(2):78-86 PubMed

Antimicrob Agents Chemother. 1993 Dec;37(12):2540-4 PubMed

Folia Biol (Praha). 1993;39(3):136-41 PubMed

Folia Biol (Praha). 1993;39(3):142-9 PubMed

Membr Biochem. 1978;2(1):17-46 PubMed

Nature. 1970 Aug 15;227(5259):680-5 PubMed

Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1499-503 PubMed

J Biol Chem. 1991 Apr 15;266(11):6915-8 PubMed

Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4961-5 PubMed

J Biol Chem. 1971 Mar 25;246(6):1828-33 PubMed

J Cell Physiol. 1971 Apr;77(2):157-68 PubMed

Proc Natl Acad Sci U S A. 1973 Nov;70(11):3170-4 PubMed

J Biol Chem. 1975 Dec 10;250(23):8889-92 PubMed

Nature. 1976 Oct 14;263(5578):596-7 PubMed

Mol Pharmacol. 1978 Mar;14(2):299-305 PubMed

J Biol Chem. 1979 Oct 25;254(20):9973-5 PubMed

J Histochem Cytochem. 1979 Dec;27(12):1596-603 PubMed

Biochim Biophys Acta. 1982 Jul 28;689(2):249-60 PubMed

J Biol Chem. 1985 Nov 5;260(25):13442-9 PubMed

J Biol Chem. 1986 Jan 5;261(1):172-7 PubMed

Biochem J. 1985 Dec 15;232(3):859-62 PubMed

Nature. 1986 Oct 2-8;323(6087):464-7 PubMed

J Biol Chem. 1986 Nov 25;261(33):15416-23 PubMed

Clin Exp Immunol. 1986 Oct;66(1):158-65 PubMed

Antimicrob Agents Chemother. 1987 Feb;31(2):337-9 PubMed

Antimicrob Agents Chemother. 1987 Sep;31(9):1431-3 PubMed

Biochemistry. 1987 Sep 8;26(18):5703-9 PubMed

Antiviral Res. 1987 Dec;8(5-6):261-72 PubMed

Cancer Res. 1988 Aug 1;48(15):4266-71 PubMed

Proc Natl Acad Sci U S A. 1989 Jan;86(1):332-6 PubMed

-CH2- lengthening of the internucleotide linkage in the ApA dimer can improve its conformational compatibility with its natural polynucleotide counterpart