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Synthesis and antiretroviral activity of phospholipid analogs of azidothymidine and other antiviral nucleosides.

Open AccessPublished:April 15, 1990DOI:https://doi.org/10.1016/S0021-9258(19)39299-3
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      Treatment of acquired immunodeficiency syndrome with azidothymidine (AZT, zidovudine) reduces p24 antigenemia, increases CD4 lymphocyte counts, reduces the frequency and severity of opportunistic infections and prolongs life. However, AZT and other dideoxynucleosides do not diminish the ability to isolate human immunodeficiency virus (HIV) from peripheral blood mononuclear cells. Failure to clear infectious virus may be due to inadequate inhibition of virus production by macrophages, a major reservoir of HIV infection. Cells of the macrophage lineage take up large amounts of parenterally administered liposomal material. To direct larger proportions of antiretroviral nucleosides to this important HIV reservoir, we synthesized phosphatidylAZT, AZT diphosphate dipalmitin, phosphatidylddC and phosphatidylddT, novel phospholipid prodrugs which are readily incorporated into phospholipid bilayers. These liposomal liponucleotides were shown to have antiretroviral activity in HIV-infected U937 and CEM cells. In vivo, it is anticipated that liposomes containing the antiretroviral liponucleotides will be taken up in large proportion by macrophages. This property would appear to make phosphatidylAZT and the related compounds promising candidate agents with a special potential to target drug to the macrophage reservoir of HIV infection, thereby reducing the toxicity of the antiviral nucleosides to other cells.

      REFERENCES

        • Barre-Sinoussi F.
        • Chermann J.C.
        • Rey R.
        • Rey F.
        • Nugeyre M.T.
        • Chamaret S.
        • Gruest J.
        • Dauguet C.
        • Axler-Blin C.
        • Vezinet-Brun F.
        • Rouzioux C.
        • Rozenbaux W.
        • Montagner L.
        Science. 1983; 220: 868-871
        • Gallo R.C.
        • Salahuddin S.Z.
        • Popovic M.
        • Shearer G.
        • Kaplan M.
        • Hayes B.
        • Palker T.
        • Redfield R.
        • Oleske J.
        • Safai B.
        • Whites G.
        • Foster P.
        • Markham P.
        Science. 1984; 224: 500-503
        • Levy J.A.
        • Hoffman A.D.
        • Kramer A.D.
        • Landis J.
        • Shimabukuro J.
        • Oshiro L.
        Science. 1984; 225: 840-842
        • Mitsuya H.
        • Weinhold K.J.
        • Furman P.A.
        • St. Clair M.H.
        • Furman P.
        • Nusinoff-Lehrman S.
        • Gallo R.
        • Bolognesi D.
        • Barry D.W.
        • Broder S.
        Proc. Natl. Acad. Sci. U. S. A. 1985; 82: 7096-7100
        • Furman P.A.
        • Fyfe J.A.
        • St. Clair M.H.
        • Weinhold K.
        • Rideout J.L.
        • Freeman G.A.
        • Lehrman S.N.
        • Bolognesi D.P.
        • Broder S.
        • Mitsuya H.
        • Barry D.W.
        Proc. Natl. Acad. Sci. U. S. A. 1986; 83: 8333-8337
        • Mitsuya H.
        • Broder S.
        Proc. Natl. Acad. Sci. U. S. A. 1986; 83: 1911-1915
        • Fischl M.A.
        • Richman D.D.
        • Grieco M.H.
        • Gottlieb M.S.
        • Volberding P.
        • Laskin O.
        • Leedom J.
        • Groopman J.
        • Mildvan D.
        • Schooley R.
        • Jackson G.
        • Durack D.
        • King D.
        N. Engl. J. Med. 1987; 317: 185-191
        • Merigan T.C.
        • Skowron G.
        • Bozzette S.A.
        • Richman D.
        • Uttamchandani R.
        • Fischi M.
        • Schooley R.
        • Hirsch M.
        • Soo W.
        • Petinelli C.
        • Schaumburg H.
        • ddC Study Group of the AIDS Clinical Trials Group
        Ann. Int. Med. 1989; 110: 189-194
        • Spector S.A.
        • Kennedy C.
        • McCutchan J.A.
        • Bozzetti S.E.
        • Straube R.G.
        • Connor D.
        • Richman D.D.
        J. Infect. Dis. 1989; 159: 822-829
        • Richman D.D.
        • Fischl M.A.
        • Grieco M.H.
        • Gottlieb M.S.
        • Volberding P.
        • Laskin O.
        • Leedom J.
        • Durack D.T.
        • Groopman J.
        • Mildvan D.
        • Hirsch M.
        • Jackson G.
        • Nusinoff-Lehrman S.
        N. Engl. J. Med. 1987; 317: 192-197
        • Ho D.D.
        • Rota T.R.
        • Hirsch M.S.
        J. Clin. Invest. 1986; 77: 1712-1715
        • Nicholson J.K.A.
        • Gross G.D.
        • Callaway C.S.
        • McDougal J.S.
        J. Immunol. 1986; 137: 323-329
        • Salahuddin S.Z.
        • Rose R.M.
        • Groopman J.E.
        • Markham P.D.
        • Gallo R.C.
        Blood. 1986; 68: 281-284
        • Gartner S.
        • Markovits P.
        • Markovitz D.M.
        • Kaplan M.H.
        • Gallo R.C.
        • Popovic M.
        Science. 1986; 233: 215-219
        • Richman D.D.
        • Kornbluth R.S.
        • Carson D.A.
        J. Exp. Med. 1987; 166: 1144-1149
        • Perno C.-F.
        • Yarchoan R.
        • Cooney D.A.
        • Hartman N.
        • Gartner S.
        • Popovic M.
        • Hao Z.
        • Gerrard T.
        • Wilson Y.
        • Johns D.
        • Broder S.
        J. Exp. Med. 1988; 168: 1111-1125
        • Epstein L.G.
        • Sharer L.R.
        • Cho E.-S.
        • Myenhofer M.
        • Navia B.A.
        • Price R.W.
        AIDS Res. 1984; 14: 447-454
        • Chayt K.J.
        • Harper M.E.
        • Marselle L.M.
        • Lewin E.B.
        • Rose R.N.
        • Oleske J.M.
        • Epstein L.G.
        • Wong-Staal F.
        • Gallo R.C.
        J. Am. Med. Assoc. 1986; 256: 2356-2359
        • Stoler M.H.
        • Eskin T.A.
        • Benn S.
        • Angerer R.C.
        • Angerer L.M.
        J. Am. Med. Assoc. 1986; 256: 2360-2364
        • Koenig S.
        • Gendelman H.E.
        • Orenstein J.M.
        • Dal Canto M.
        • Pezeshkpour G.
        • Yungbluth M.
        • Sanotta F.
        • Aksamit A.
        • Martin M.
        • Fanci T.
        Science. 1986; 233: 1089-1093
        • Wiley C.A.
        • Schrier R.D.
        • Nelson J.A.
        • Lampert P.A.
        • Oldstone M.B.A.
        Proc. Natl. Acad. Sci. U. S. A. 1986; 83: 7089-7093
        • Black C.D.V.
        • Watson G.J.
        • Ward R.J.
        Trans. R. Soc. Trop. Med. Hyg. 1977; 71: 550-552
        • Alving C.R.
        • Steck E.A.
        • Champan W.L.
        • Waits V.B.
        • Hendricks L.D.
        • Swartz G.M.
        • Hanson W.L.
        Proc. Natl. Acad. Sci. U. S. A. 1978; 75: 2959-2963
        • Aneja R.
        • Chadha J.S.
        • Davies A.P.
        Biochim. Biophys. Acta. 1970; 218: 102-111
        • Aneja R.
        • Chadha J.S.
        Biochim. Biophys. Acta. 1971; 248: 455-457
        • Van den Bosch H.
        Biochim. Biophys. Acta. 1980; 604: 191-246
        • Dawson R.M.C.
        Biochem. J. 1956; 62: 689-693
        • Morash S.C.
        • Cook H.W.
        • Spence M.W.
        Biochim. Biophys. Acta. 1988; 961: 194-202
        • Martin T.W.
        • Michaelis K.C.
        Biochem. Biophys. Res. Commun. 1988; 157: 1271-1279
        • Agranoff B.W.
        • Suomi W.D.
        Biochem. Prep. 1967; 10: 47-51
        • Ter Schegget J.
        • van den Bosch H.
        • van Baak M.A.
        • Hostetler K.Y.
        • Borst P.
        Biochim. Biophys. Acta. 1971; 239: 234-242
        • Poorthuis B.J.H.M.
        • Hostetler K.Y.
        Biochim. Biophys. Acta. 1976; 431: 408-415
        • MacCoss M.
        • Ryia E.K.
        • Matsushita T.
        Biochem. Biophys. Res. Commun. 1978; 85: 714-723
        • Turcotte J.G.
        • Srivastava S.P.
        • Meresak W.A.
        • Rizkalla B.A.
        • Louzon F.
        • Wunz T.P.
        Biochim. Biophys. Acta. 1980; 619: 604-618
        • Ryia E.K.
        • Ross J.R.
        • Matsushita T.
        • MacCoss M.
        • Hong C.I.
        • West C.R.
        J. Med. Chem. 1982; 25: 1322-1329
        • Van den Bosch H.
        Annu. Rev. Biochem. 1974; 43: 243-277
        • Hostetler K.Y.
        Hawthorne J.N. Comprehensive Biochemistry. Elsevier-North Holland, Amsterdam1982: 481-492
        • Rittenhouse H.G.
        • Seguin E.B.
        • Fischer S.K.
        • Agranoff B.W.
        J. Neurochem. 1981; 36: 991-999
        • Raetz C.R.H.
        • Hirschberg C.B.
        • Dowhan W.
        • Wickner W.T.
        • Kennedy E.P.
        J. Biol. Chem. 1972; 247: 2245-2247
        • Bligh E.G.
        • Dyer W.J.
        Can. J. Biochem. 1959; 37: 911-917