Inhibition of HIV-replication by 3′-fluoro-modified nucleosides with low cytotoxicity

Matthes, E.; Lehmann, Christian; Janta-Lipinski, M. Von; Scholz, D.

doi:10.1016/0006-291x(89)91096-6

Cited by 34 publications

(24 citation statements)

References 11 publications

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“…The difference in substrate efficiency between AZTTP and 935U83 triphosphate was consistent with the observed fivefold difference in their Ki values as inhibitors of RT-catalyzed incorporation of dTMP into poly(rA)-oligo(dT). Previously, Matthes et al (46) reported that the 'C50 of 935U83 triphosphate as an inhibitor of dTMP incorporation into poly(rA)-oligo(dT) was slightly lower than that of AZT7fP. 935U83 had a relatively low toxicity profile in vivo.…”

Section: Resultsmentioning

confidence: 99%

5-Chloro-2',3'-dideoxy-3'-fluorouridine (935U83), a selective anti-human immunodeficiency virus agent with an improved metabolic and toxicological profile

Daluge

Purifoy

Savina

et al. 1994

Antimicrob Agents Chemother

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5-Chloro-2',3'-dideoxy-3'-fluorouridine (935U83) is a selective anti-human immunodeficiency virus (H1V) agent. When tested in phytohemagglutinin-stimulated normal human peripheral blood lymphocytes against fresh clinical isolates of HIV type 1 (HIV-1) obtained from patients naive to AZT (3'-azido-3'-deoxythymidine [zidovudine]), 935U83 inhibited virus growth with an average 50%v inhibitory concentration (IC50) of 1.8 ,uM; corresponding IC,Os were 0.10 ,uM for FLT (3'-deoxy-3'-fluorothymidine) and 0.23, 0.49, and 0.03 ,uM for the approved agents AZT, ddI (2',3'-dideoxyinosine), and ddC (2',3'-dideoxycytosine), respectively. Importantly, 935U83 retained activity against HIV strains that were resistant to AZT, ddl, or ddC. Of additional interest, we were unable to generate virus which was resistant to 935U83 by passaging either HXB2 (AZT-sensitive) or RTMC (AZT-resistant) strains in the presence of high concentrations of 935U83. The anabolic profile of 935U83 was similar to that of AZT, and 93SU83 triphosphate was a potent inhibitor of HIV-1 reverse transcriptase. Pharmacokinetic evaluation showed good oral bioavailability (86% in mice and 60%Yo in monkeys) and less extensive metabolism to the glucuronide relative to AZT. 935U83 showed low toxicity. In an in vitro assay for toxicity to a human erythrocyte progenitor, erythroid burst-forming unit (BFU-E), the IC50 for 935U83 (>400 ,uM) was more than 1,000-fold those of FLT (0.07 ,uM) and AZT (0.30 ,uM). Mild reversible reductions in erythrocytes and associated parameters were seen in mice dosed orally with 2,000 mg of 935U83 per kg per day for 1 and 6 months. In monkeys dosed orally with up to 700 mg/kg/day for 1 and 6 months, the only possible treatment-related finding was cataracts in 1 of 12 animals given the intermediate dose of 225 mg/kg/day. At the highest doses in mice and monkeys, maximal concentrations in plasma were more than 100-fold the anti-H1V IC50s against clinical isolates. This safety profile in animals compares very favorably with that of any of the anti-HIV drugs approved to date and has led us to begin evaluation of 935U83 in patients with HIV infection.

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Section: Resultsmentioning

confidence: 99%

5-Chloro-2',3'-dideoxy-3'-fluorouridine (935U83), a selective anti-human immunodeficiency virus agent with an improved metabolic and toxicological profile

Daluge

Purifoy

Savina

et al. 1994

Antimicrob Agents Chemother

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“…In the present study we investigated whether stimulation of the physiologically functioning antiviral protection system (2-5A synthetase/RNase L) by the mismatched dsRNA, poly(I)'poly(C 12U) [Ampligen], causes an augmentation of the anti-HIV-1 effects displayed by inhibitors of RT (we selected as an example FddThd, that compound which had been studied in our groups extensively [Matthes et al, 1989]) and the viral regulatory proteins Tat and Rev (antisenseODN and pyronin Y) in vitro. The results show synergy in all combinations with poly(I)·poly(C 12U).…”

Section: Resultsmentioning

confidence: 99%

“…Suhadolnik, personal communication). 2',3'-Oideoxy-3'-fluorothymidine (FddThd) was obtained as described (Matthes et al, 1989).…”

Section: Discussionmentioning

confidence: 99%

Synergistic Anti-Human Immunodeficiency Viral (HIV-1) Effect of the Immunomodulator Ampligen (Mismatched Double-Stranded RNA) with Inhibitors of Reverse Transcriptase and HIV-1 Regulatory Proteins

Ushijima

Tsiapalis

Daum

et al. 1993

Antivir Chem Chemother

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The potent antiviral effect of double stranded RNA, such as the mismatched poly(l)·poly(C12U) [Ampligen], 2′,3′-dideoxy-3′-fluorothymidine (FddThd) and antisense oligodeoxynucleotides (ODN) has been established in in vitro systems using cells infected with the human immunodeficiency virus type 1 (HIV-1). We report here that the immunomodulator poly(l)·poly(C12U) interacts synergistically with (1) the reverse transcriptase inhibitor FddThd (FIC value: 0.43), (2) the modified (5′- and 3′-end capped thioates) antisense ODN-4 directed against the splice acceptor site of the HIV-1/ tat gene (FIC value: 0.66) and (3) also with pyronin Y, a compound which prevents binding of HIV-1 Rev protein to the HIV-1 RRE element. These data suggest that combinations of poly(l)·poly(C12U), a stimulator of the natural antiviral protection system of the cells, with compounds targeting HIV1-specific processes should be considered as candidate treatments of AIDS patients.

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“…Their pharmacokinetic properties have also been studied in detail (Balis et al, 1989;Boudinot et al, 1990;Good and de Miranda, 1992;Ljungdahl-Stahle et al, 1992;Sandstrom and Oberg, 1993;Stahle et al, 1993). 5-Chloro-2',3'-dideoxy-3'-fluorouridine as a selective anti-human immunodeficiency virus (HIV) agent has been also studied by Balzarini et al (1989) ;Matthes et al (1989);and Daluge et al (1994).…”

Section: Introductionmentioning

confidence: 99%

Distribution to the Brain and Protein Binding of 3′and 5-Substituted 2′,3′-Dideoxyuridine Derivatives, Studied by Microdialysis

Borg

Zhou

Johansson

et al. 1997

Antivir Chem Chemother

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SummaryThe aim of this study was to investigate a series of 3' and 5-substituted 2',3' -dideoxyuridine derivatives (ddUD) with respect to plasma protein binding, halflife and distribution across the blood-brain barrier in the rat. The microdialysis technique was used to study protein binding in human plasma (in vitro), and to sample the extracellular space of rats with microdialysis probes implanted into the striatum of the brain and the gastrocnemic muscle (in vivo). The compounds were analysed by HPLC with UV-detection. The octanol/water partition coefficients of the dduD varied from 0.08-0.84. The protein binding of the ddUDswas approximately 80%. After s.c. administration (25 or 50 mg kg-1 ), the brain and muscle extracellular levels differed; brain levels were 0.18-0.36 o] peripheral (muscle) concentrations. A multivariate analysis, which included data on zidovudine, alovudine and thymidine, demonstrated a relationship between the physicochemical and some of the phormacokinetic properties of uridine analogues. The analysis shows that half-life and protein binding increases with decreasing pK a . However, penetration to the brain is not correlated with the partition into octano!. It is concluded that the transport to the brain is not primarily dependent upon passive diffusion over a lipophilic barrier but, rather, to other chemical properties of the dduDs. This is suggestive of a specific transport mechanism, e.g. the thymidine carrier.

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Inhibition of HIV-replication by 3′-fluoro-modified nucleosides with low cytotoxicity

Cited by 34 publications

References 11 publications

5-Chloro-2',3'-dideoxy-3'-fluorouridine (935U83), a selective anti-human immunodeficiency virus agent with an improved metabolic and toxicological profile

5-Chloro-2',3'-dideoxy-3'-fluorouridine (935U83), a selective anti-human immunodeficiency virus agent with an improved metabolic and toxicological profile

Synergistic Anti-Human Immunodeficiency Viral (HIV-1) Effect of the Immunomodulator Ampligen (Mismatched Double-Stranded RNA) with Inhibitors of Reverse Transcriptase and HIV-1 Regulatory Proteins

Distribution to the Brain and Protein Binding of 3′and 5-Substituted 2′,3′-Dideoxyuridine Derivatives, Studied by Microdialysis

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