Antiretroviral activities of acyclic nucleoside phosphonates [9-(2-phosphonylmethoxyethyl)adenine, 9-(2-phosphonylmethoxyethyl)guanine, (R)-9-(2-phosphonylmethoxypropyl)adenine, and MDL 74,968] in cell cultures and murine sarcoma virus-infected newborn NMRI mice.
From a side-by-side comparative study, the acyclic nucleoside phosphonates (R)-9-(2-phosphonylmethoxypropyl)adenine [(R)-PMPA] and 9-(2-methylidene-3-phosphonomethoxypropyl)guanine (MDL 74,968) proved more selective in their inhibitory effect on human immunodeficiency virus types 1 and 2, feline immunodeficiency virus, and Moloney murine sarcoma virus (MSV) in cell cultures than the 9-(2-phosphonylmethoxyethyl) derivatives of adenine (PMEA) and guanine (PMEG). In particular, PMEG proved quite toxic. PMEA, (R)-PMPA, and MDL 74,968 afforded a marked delay in MSV-induced tumor initiation in MSV-infected newborn NMRI mice and substantially delayed associated animal death at doses as low as 4 to 10 mg/kg of body weight. Treatment of the NMRI mice with PMEA, (R)-PMPA, and MDL 74,968 at 25 or 50 mg/kg resulted in a high percentage of long-term survivors.
Balzarini
J
J
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
Vahlenkamp
T
T
Egberink
H
H
Hartmann
K
K
Witvrouw
M
M
Pannecouque
C
C
Casara
P
P
Navé
J F
JF
De Clercq
E
E
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000831:Animals, Newborn; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D002460:Cell Line; D005347:Fibroblasts; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000494:pharmacology / Q000627:therapeutic use; D012190:Retroviridae / Q000187:drug effects*; D012192:Retroviridae Infections / Q000188:drug therapy* / Q000821:virology; D009053:Sarcoma Viruses, Murine; D000068698:Tenofovir
D000998:Antiviral Agents; D063065:Organophosphonates; D009943:Organophosphorus Compounds; C063380:9-((2-phosphonylmethoxy)ethyl)guanine; C101422:9-(2-methylidene-3-(phosphonomethoxy)propyl)guanine; D006147:Guanine; C053001:adefovir; D000068698:Tenofovir; D000225:Adenine