Abstract
Twenty-six PPi analogs were tested for inhibitory effects on human T-lymphotropic virus type III reverse transcriptase. The structural requirements for inhibition and mechanism of action of the most active inhibitors have been investigated. Foscarnet (phosphonoformic acid) was the most potent inhibitor of human T-lymphotropic virus type III reverse transcriptase with 50% inhibition at 0.5 microM. The mechanism was a noncompetitive type of inhibition of a (riboadenylic acid)n . (deoxythymidylic acid)12-18 [(rA)n(dT)12-18]-directed transcription at varied dTTP concentration. At constant substrate (dTTP) concentration and varied amounts of template, (rA)n(dT)12-18, the inhibitory action of foscarnet was of an uncompetitive type. The same pattern of inhibition was seen when the less active inhibitor carbonyldiphosphonate was studied under identical conditions. The structural requirements for inhibition of human T-lymphotropic virus type III reverse transcriptase by PPi analogs were similar to those shown by other reverse transcriptases.
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- Basu A., Modak M. J. Observations on the suramin-mediated inhibition of cellular and viral DNA polymerases. Biochem Biophys Res Commun. 1985 May 16;128(3):1395–1402. doi: 10.1016/0006-291x(85)91095-2. [DOI] [PubMed] [Google Scholar]
- Eriksson B., Larsson A., Helgstrand E., Johansson N. G., Oberg B. Pyrophosphate analogues as inhibitors of herpes simplex virus type 1 DNA polymerase. Biochim Biophys Acta. 1980 Mar 28;607(1):53–64. doi: 10.1016/0005-2787(80)90220-8. [DOI] [PubMed] [Google Scholar]
- Eriksson B., Stening G., Oberg B. Inhibition of reverse transcriptase activity of avian myeloblastosis virus by pyrophosphate analogues. Antiviral Res. 1982 May;2(1-2):81–95. doi: 10.1016/0166-3542(82)90028-6. [DOI] [PubMed] [Google Scholar]
- Gonda M. A., Wong-Staal F., Gallo R. C., Clements J. E., Narayan O., Gilden R. V. Sequence homology and morphologic similarity of HTLV-III and visna virus, a pathogenic lentivirus. Science. 1985 Jan 11;227(4683):173–177. doi: 10.1126/science.2981428. [DOI] [PubMed] [Google Scholar]
- Mitsuya H., Popovic M., Yarchoan R., Matsushita S., Gallo R. C., Broder S. Suramin protection of T cells in vitro against infectivity and cytopathic effect of HTLV-III. Science. 1984 Oct 12;226(4671):172–174. doi: 10.1126/science.6091268. [DOI] [PubMed] [Google Scholar]
- Oberg B. Antiviral effects of phosphonoformate (PFA, foscarnet sodium). Pharmacol Ther. 1982;19(3):387–415. doi: 10.1016/0163-7258(82)90074-2. [DOI] [PubMed] [Google Scholar]
- Popovic M., Sarngadharan M. G., Read E., Gallo R. C. Detection, isolation, and continuous production of cytopathic retroviruses (HTLV-III) from patients with AIDS and pre-AIDS. Science. 1984 May 4;224(4648):497–500. doi: 10.1126/science.6200935. [DOI] [PubMed] [Google Scholar]
- Sandstrom E. G., Kaplan J. C., Byington R. E., Hirsch M. S. Inhibition of human T-cell lymphotropic virus type III in vitro by phosphonoformate. Lancet. 1985 Jun 29;1(8444):1480–1482. doi: 10.1016/s0140-6736(85)92255-x. [DOI] [PubMed] [Google Scholar]
- Sarin P. S., Taguchi Y., Sun D., Thornton A., Gallo R. C., Oberg B. Inhibition of HTLV-III/LAV replication by foscarnet. Biochem Pharmacol. 1985 Nov 15;34(22):4075–4079. doi: 10.1016/0006-2952(85)90392-2. [DOI] [PubMed] [Google Scholar]
- Sundquist B., Larner E. Phosphonoformate inhibition of visna virus replication. J Virol. 1979 Jun;30(3):847–851. doi: 10.1128/jvi.30.3.847-851.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sundquist B., Oberg B. Phosphonoformate inhibits reverse transcriptase. J Gen Virol. 1979 Nov;45(2):273–281. doi: 10.1099/0022-1317-45-2-273. [DOI] [PubMed] [Google Scholar]