       Document 0961
 DOCN  M9650961
 TI    Enhancement of the anti-HIV-1 activity of ddAdo by coformycin, EHNA and
       deaza-EHNA derivatives.
 DT    9505
 AU    Marongiu ME; Pani A; Tinti E; Grifantini M; Franchetti P; Cristalli G;
       La Colla P; Dipartimento di Biologia Sperimentale, Universita di
       Cagliari,; Italy.
 SO    New Microbiol. 1995 Oct;18(4):359-70. Unique Identifier : AIDSLINE
       MED/96156480
 AB    2',3'-dideoxyadenosine (ddAdo) and 2',3'-dideoxyinosine (ddIno) are
       potent and selective inhibitors of the replication of the human
       immunodeficiency virus type 1 (HIV1) in several cell culture systems.
       Equipotent in terms of antiviral activity, both compounds selectively
       inhibit the reverse transcription of HIV-1 by virtue of their conversion
       into ddATP. In human lymphoid cells ddAdo is converted to the active
       metabolite, ddATP, but it also undergoes rapid deamination, via
       adenosine deaminase, to form ddIno. ddIno, like ddAdo, gives rise to
       dideoxynucleotides of the dideoxy-adenylate series (ddAMP, ddADP and
       ddATP), as well as to IMP and to adenylate ribonucleotides. With the
       main object of blocking the deamination of ddAdo, we studied its
       anti-HIV-1 activity in the presence of different adenosine deaminase
       inhibitors, namely Coformycin (CF), 9-(erythro-2-hydroxy-3-nonyl)
       adenine (EHNA) and some deaza-EHNA derivatives. In contrast with reports
       on 2'-deoxycoformycin (Cooney et al., 1987), the adenosine deaminase
       inhibitors tested by us showed a significant increase in the antiviral
       activity of ddAdo, but not of ddIno. Enhancement was obtained with EHNA
       and CF concentrations up to 250 and > 12,500 times lower than their
       respective maximum non toxic doses. In combination with EHNA or CF,
       ddAdo could be used at concentrations up to ten times lower than those
       required to obtain the same degree of inhibition when ddAdo (or ddIno)
       was used alone. The use of EHNA or CF in combination with ddAdo at
       concentrations that inhibit the multiplication of HIV-1, allowed
       uninfected cells to maintain their normal multiplication rates. In fact,
       in combination experiments, cytotoxic effects were evident only with
       doses of EHNA, or CF and ddAdo 10 to 100 or more times higher than those
       required to inhibit HIV-1 significantly. The in vivo implications of
       these results for anti-HIV chemotherapy are discussed.
 DE    Adenine/*ANALOGS & DERIVATIVES/ADMINISTRATION & DOSAGE  Adenosine
       Deaminase/*ANTAGONISTS & INHIB  Antiviral Agents/*ADMINISTRATION &
       DOSAGE  Cell Line  Coformycin/*ADMINISTRATION & DOSAGE  Comparative
       Study  Dideoxyadenosine/*ADMINISTRATION & DOSAGE  Drug Screening  Drug
       Synergism  Enzyme Inhibitors/*ADMINISTRATION & DOSAGE  Human
       HIV-1/*DRUG EFFECTS/PHYSIOLOGY  Support, Non-U.S. Gov't  Virus
       Replication/DRUG EFFECTS  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

