MDL 74,968, a new acyclonucleotide analog: activity against human immunodeficiency virus in vitro and in the hu-PBL-SCID.beige mouse model of infection.
The novel acyclonucleotide derivative of guanine, 9-[2-methylidene-3-(phosphonomethoxy)propyl] guanine (MDL 74,968), had antiviral activity comparable to those of 9-(2-phosphonomethoxyethyl) adenine (PMEA) and 2',3'-dideoxyinosine against laboratory strains of both human immunodeficiency virus (HIV) types 1 and 2 cultured in MT-4 cells and several clinical HIV isolates cultured in human peripheral blood mononuclear cells (PBMCs). MDL 74,968 was at least fourfold less toxic than PMEA to MT-4 cells or PBMCs, thereby producing a more favorable in vitro selectivity index for the former compound. Studies of acute toxicity in CD-1 mice showed that MDL 74,968 was not toxic at doses of 1,600 mg/kg of body weight via the intraperitoneal route or at doses of 500 mg/kg via the intravenous route. Furthermore, no adverse effects of MDL 74,968 were apparent when mice were treated at doses of 200 mg/kg twice daily for 5 days. Treatment by continuous subcutaneous infusion of MDL 74,968 or PMEA at the daily dose of 20 mg/kg in the hu-PBL-SCID.beige murine model of HIV infection significantly reduced the severity of infection compared with that in placebo-treated controls. Quantitation of virus recovery by endpoint titration of spleen cells in coculture with mitogen-activated PBMCs demonstrated that MDL 74,968 as well as PMEA significantly reduced the amount of virus (P < 0.02). Moreover, by using DNA extracted from spleens, the mean HIV:HLA PCR product ratio, which takes into account individual variation in immune system reconstitution, were 0.50 and 0.40 for MDL 74,968 and PMEA treatments, respectively, whereas animals receiving the placebo control had significantly higher levels of HIV proviral DNA (mean 0.78; P < 0.02). Taken together, these promising findings suggest that an orally bioavailable prodrug of MDL 74,968 should be developed for the treatment of HIV infection.
Bridges
C G
CG
Medical Research Council Collaborative Centre, London, United Kingdom. g-bridge@nimr.mrc.ac.uk
Taylor
D L
DL
Ahmed
P S
PS
Brennan
T M
TM
Hornsperger
J M
JM
Navé
J F
JF
Casara
P
P
Tyms
A S
AS
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D002460:Cell Line / Q000187:drug effects / Q000821:virology; D002478:Cells, Cultured; D004279:DNA, Viral / Q000378:metabolism; D016049:Didanosine / Q000494:pharmacology / Q000633:toxicity; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects*; D015498:HIV-2 / Q000187:drug effects*; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009000:Monocytes / Q000821:virology; D063065:Organophosphonates; D013154:Spleen / Q000821:virology; D013601:T-Lymphocytes / Q000187:drug effects / Q000821:virology; D015215:Zidovudine / Q000494:pharmacology / Q000633:toxicity
D000998:Antiviral Agents; D004279:DNA, Viral; D063065:Organophosphonates; C101422:9-(2-methylidene-3-(phosphonomethoxy)propyl)guanine; D015215:Zidovudine; D006147:Guanine; C053001:adefovir; D000225:Adenine; D016049:Didanosine