DIFFERENTIAL ANTIHERPESVIRUS AND ANTIRETROVIRUS EFFECTS OF THE (S) AND (R) ENANTIOMERS OF ACYCLIC NUCLEOSIDE PHOSPHONATES - POTENT AND SELECTIVE INVITRO AND INVIVO ANTIRETROVIRUS ACTIVITIES OF (R)-9-(2-PHOSPHONOMETHOXYPROPYL)-2,6-DIAMINOPURINE

被引:302
作者
BALZARINI, J [1 ]
HOLY, A [1 ]
JINDRICH, J [1 ]
NAESENS, L [1 ]
SNOECK, R [1 ]
SCHOLS, D [1 ]
DECLERCQ, E [1 ]
机构
[1] CZECHOSLOVAK ACAD SCI, INST ORGAN CHEM & BIOCHEM, CS-16610 PRAGUE 6, CZECHOSLOVAKIA
关键词
D O I
10.1128/AAC.37.2.332
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
The (S)- and (R)-enantiomers of acyclic purine nucleoside phosphonate analogs (i.e., 3-hydroxy-2-phosphonomethoxypropyl [HPMP] derivatives, 3-fluoro-2-phosphonomethoxypropyl [FPMP] derivatives, and 2-phosphonomethoxypropyl [PMP] derivatives of adenine [A], 2-aminopurine, 2,6-diaminopurine [DAP], and guanine [G]) have been synthesized and evaluated for antiviral activity. As a rule, the HPMP derivatives proved effective against DNA viruses but not RNA viruses or retroviruses. In particular, (S)-HPMPA, (S)-HPMPDAP, and (R)- and (S)-HPMPG were exquisitely inhibitory to herpes simplex virus type 1 (50% effective concentrations, 0.63, 0.22, 0.10, and 0.66 muM, respectively). The FPMP and PMP derivatives showed marked inhibitory activities against retroviruses but not DNA viruses. The (S)-enantiomer of FPMPA and the (R)-enantiomer of PMPA were approximately 30- to 100-fold more effective against human immunodeficiency virus and Moloney murine sarcoma virus (MSV) than their enantiomeric counterparts. In contrast, both (S)- and (R)-enantiomers of the DAP and G derivatives proved equally effective against retroviruses, except for (R)-PMPDAP, which was 15- to 40-fold more inhibitory than (S)-PMPDAP. (R)-PMPDAP emerged as the most potent and selective inhibitor of MSV-induced transformation of murine C3H/3T3 cells and human immunodeficiency virus-induced cytopathicity in MT-4 and CEM cells (50% effective concentration, approximately 0.1 to 0.6 muM). When administered intraperitoneally at a single dose as low as 2 mg/kg, (R)-PMPDAP efficiently decreased MSV-induced tumor formation in newborn NMRI mice and significantly increased the survival time of MSV-infected mice. In addition, upon oral administration to MSV-infected mice, (R)-PMPDAP showed marked antiretroviral efficacy.
引用
收藏
页码:332 / 338
页数:7
相关论文
共 26 条
  • [1] INVITRO ACTIVITY OF (S)-9-(3-HYDROXY-2-PHOSPHONYLMETHOXYPROPYL)-ADENINE AGAINST NEWLY ISOLATED CLINICAL VARICELLA-ZOSTER VIRUS-STRAINS
    BABA, M
    KONNO, K
    SHIGETA, S
    DECLERCQ, E
    [J]. EUROPEAN JOURNAL OF CLINICAL MICROBIOLOGY & INFECTIOUS DISEASES, 1987, 6 (02) : 158 - 160
  • [2] MARKED INVIVO ANTIRETROVIRUS ACTIVITY OF 9-(2-PHOSPHONYLMETHOXY-ETHYL)ADENINE, A SELECTIVE ANTI-HUMAN IMMUNODEFICIENCY VIRUS AGENT
    BALZARINI, J
    NAESENS, L
    HERDEWIJN, P
    ROSENBERG, I
    HOLY, A
    PAUWELS, R
    BABA, M
    JOHNS, DG
    DECLERCQ, E
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1989, 86 (01) : 332 - 336
  • [3] 9-(2-PHOSPHONYLMETHOXYETHYL)ADENINE (PMEA) EFFECTIVELY INHIBITS RETROVIRUS REPLICATION INVITRO AND SIMIAN IMMUNODEFICIENCY VIRUS-INFECTION IN RHESUS-MONKEYS
    BALZARINI, J
    NAESENS, L
    SLACHMUYLDERS, J
    NIPHUIS, H
    ROSENBERG, I
    HOLY, A
    SCHELLEKENS, H
    DECLERCQ, E
    [J]. AIDS, 1991, 5 (01) : 21 - 28
  • [4] 9-[(2RS)-3-FLUORO-2-PHOSPHONYLMETHOXYPROPYL] DERIVATIVES OF PURINES - A CLASS OF HIGHLY SELECTIVE ANTIRETROVIRAL AGENTS INVITRO AND INVIVO
    BALZARINI, J
    HOLY, A
    JINDRICH, J
    DVORAKOVA, H
    HAO, Z
    SNOECK, R
    HERDEWIJN, P
    JOHNS, DG
    DECLERCQ, E
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1991, 88 (11) : 4961 - 4965
  • [5] HIV-1-SPECIFIC REVERSE-TRANSCRIPTASE INHIBITORS SHOW DIFFERENTIAL ACTIVITY AGAINST HIV-1 MUTANT STRAINS CONTAINING DIFFERENT AMINO-ACID SUBSTITUTIONS IN THE REVERSE-TRANSCRIPTASE
    BALZARINI, J
    KARLSSON, A
    PEREZPEREZ, MJ
    VRANG, L
    WALBERS, J
    ZHANG, H
    OBERG, B
    VANDAMME, AM
    CAMARASA, MJ
    DECLERCQ, E
    [J]. VIROLOGY, 1993, 192 (01) : 246 - 253
  • [6] ACTIVITY OF ACYCLIC NUCLEOSIDE PHOSPHONATE ANALOGS AGAINST HUMAN-IMMUNODEFICIENCY-VIRUS IN MONOCYTE MACROPHAGES AND PERIPHERAL-BLOOD LYMPHOCYTES
    BALZARINI, J
    PERNO, CF
    SCHOLS, D
    DECLERCQ, E
    [J]. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1991, 178 (01) : 329 - 335
  • [7] BALZARINI J, IN PRESS MOL PHARM
  • [8] BALZARINI J, 1992, IN PRESS 3RD P INT S
  • [9] ISOLATION OF A NEW HUMAN RETROVIRUS FROM WEST-AFRICAN PATIENTS WITH AIDS
    CLAVEL, F
    GUETARD, D
    BRUNVEZINET, F
    CHAMARET, S
    REY, MA
    SANTOSFERREIRA, MO
    LAURENT, AG
    DAUGUET, C
    KATLAMA, C
    ROUZIOUX, C
    KLATZMANN, D
    CHAMPALIMAUD, JL
    MONTAGNIER, L
    [J]. SCIENCE, 1986, 233 (4761) : 343 - 346
  • [10] BROAD-SPECTRUM ANTI-DNA VIRUS AND ANTIRETROVIRUS ACTIVITY OF PHOSPHONYLMETHOXYALKYLPURINES AND PHOSPHONYLMETHOXYALKYLPYRIMIDINES
    DECLERCQ, E
    [J]. BIOCHEMICAL PHARMACOLOGY, 1991, 42 (05) : 963 - 972