Sage Journals: Discover world-class research

Abstract

Two thiosemicarbazone derivatives (TSCD), N-methylisatin-β-4′:4′-diethylthiosemicarbazone (M-IBDET) and N-allylisatin-β-4′:4-diallylthiosemicarbazone (A-IBDAT), were tested for their anti-feline immunodeficiency virus (FIV) activity in FL₄/FIV cells. This cell line consists of feline T-lymphocytes chronically infected with FIV. FIV production in FL₄/FIV cells was inhibited by M-IBDET and A-IBDAT. Virus inhibition was proportional to drug concentrations and time of treatment. The effective antiviral drug concentrations ranged from 0.06 to 0.64 μm for M-IBDET and from 0.45 to 8.7 μm for A-IBDAT. Tests performed to determine the therapeutic index (TI) value for each drug indicated TI values of 10 and 20 for M-IBDET and A-IBDAT, respectively. Continuous treatment of the cells with low doses of the drugs, given at constant time intervals, for a whole month succeeded in suppressing the chronic infection. Experiments directed towards understanding the mode of inhibition of FIV by TSCD indicated that A-IBDAT is involved in repression of the synthesis of the p24 structural protein of FIV. Examination of the possibility that the TSCD are also involved in suppression of the activity of HIV's tat regulatory protein showed a clear dose-responsive inhibition of HIV's tat-mediated transactivation by M-IBDET and A-IBDAT.

References

Bauer

D.J.

(1972) Thiosemicarbazones. In Chemotherapy of Virus Diseases, Vol. 1. Oxford: Pergamon Press, pp. 35–113.

Edelstein

Abramoff

Stacher

, and Teitz

(1980) New thiosemicarbazones of mono and bicyclic alpha ketolactam. Eu J Med Chem 15: 566.

Fischl

Richman

D.D.

Grieco

M.H.

Gottlieb

M.S.

Volberding

P.A.

Laskin

O.L.

Leedom

J.M.

Groopoman

J.E.

Mildvan

Schooley

R.T.

Jackson

G.G.

Durack

D.T.

, and King

(1987) The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and Aids-related complex. A double blind, placebo controlled trial. N Engl J Med 317: 185–191.

Frankel

A.D.

, and Pabo

C.O.

(1988) Cellular uptake of the Tat protein from Human Immunodeficiency Virus. Cell 55: 1189–1193.

Graham

F.L.

, and van der Eb

A.J.

(1973) A new technique for the assay of infectivity of human adeno 5 DNA. Virology 5: 456–467.

Harbour

D.A.

(1992) Feline Immunodeficiency Virus infection as a model for HIV infection in man. Rev Med Virol 2: 43–49.

J.M.

, and Hsiung

G.D.

(1989) Evaluation of new antiviral agents. In: In vitro perspectives. Antiviral Rev 11: 217–232.

Laemmli

U.K.

(1970) Cleavage of structural proteins during assembly of the head of bacteriophage T₄. Nature (London) 227: 680–685.

Mitsuya

Jarret

Matsukura

Dimarzo-Veronese

DeVico

A.L.

Sarngadharan

M.G.

Johns

D.G.

Reitz

M.S.

, and Broder

(1987) Long term inhibition of human T-lympho-tropic virus type III/lymphadenopathy-associated virus (human immunodeficiency virus) DNA synthesis and RNA expression in T cells protected by 2′,3′-dideoxynucleosides in vitro. Proc Natl Acad Sci USA 84: 2033–2037.

10.

Munn

, and Okuda

(1991) Development of IL₂ independent Feline Lymphoid cell lines chronically infected with Feline Immunodeficiency Virus: Importance for diagnostic reagents and vaccines. Intervirol 32: 361–375.

11.

O'Sullivan

P.W.

Sadler

P.W.

, and Webley

(1963) A study of chemotherapeutic activity of isatin-β-4′:4′ dialkylthiosemicarbazones against Ectromelia infection. Chemotherapia 7: 17–26.

12.

Pearson

G.D.

, and Zimmerman

E.F.

(1969) Inhibition of polio virus replication by N-methylisatin-β-4′:4′-dibutylthiosemicar-bazone. Virol 38: 641–650.

13.

Richman

D.D.

Fischl

M.A.

Grieco

M.H.

Gottlieb

M.S.

Volberding

P.A.

Laskin

O.L.

Leedome

J.M.

Groopoman

J.E.

Mildvan

Hirsch

M.S.

Jackson

G.G.

Durack

D.T.

, Nusinoff-Lehrman, S., and AZT Collaborative Working Group (1987) The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex: a double blind, placebo controlled trial. N Engl J Med 317: 192–197.

14.

Ronen

, and Teitz

(1984) Inhibition of the synthesis of Moloney leukemia virus structural proteins by N-methylisatin-β-4′:4′-diethylthiosemicarbazone. Antimicrob Agents Chemother 26: 913–916.

15.

Ronen

Nir

, and Teitz

(1985) Effect of N-methylisatin-β-4′:4′-diethylthiosemicarbazone on intracellular Moloney leukemia virus constituents. Antiviral Res 5: 249–254.

16.

Ronen

Sherman

Bar-Nun

, and Teitz

(1987) N-methylisatin-β-4′:4′-diethylthiosemi***carbazone an inhibitor of Moloney leukemia virus protein production: Characterization and In Vitro translation of viral mRNA. Antimicrob Agents Chemother 31: 1798–1802.

17.

Ronen

Rotter

, and Reisman

(1991) Expression from the murine p53 promoter is mediated by factor binding to a downstream helix-loop-helix recognition motif. Proc Natl Acad Sci USA 88: 4128–4132.

18.

Ronen

Teitz

Goldfinger

, and Rotter

(1992) Expression of wild-type and mutant p53 proteins by recombinant Vaccinia viruses. Nucleic Acid Res 20: 3435–3441.

19.

Sherman

Edelstein

Stacher

Abramoff

, and Teitz

(1980) Inhibition of Moloney leukemia virus production by N-methylisatin-β-4′:4′-diethylthiosemicarbazone. J Gen Virol 46: 195–203.

20.

Teitz

(1989) Thiosemicarbazone derivatives — potential drugs against retroviruses. Patent granted: Israel No. 77496, 1989. U.K. No. GB2184944B, 1989. USA No. 4,827,843, 1990.

21.

Teitz

Ladizensky

Barko

, and Burstein

(1993) Selective repression of v-abl coded protein by N-methylisatin-β-4′:4′-diethylthiosemicarbazone and N-allyisatin-β-4′:4′-diallylthiosemicarbazone. Antimicrob Agents Chemother 37: 2483–2485.

22.

Teitz

Barko

Abramoff

, and Ronen

(1994) The relationship between structure and anti-retroviral activity of thiosemicarbazone derivatives. Chemotherapy 76: 1–6.

23.

Yarchoan

Perno

C.F.

Thomas

R.V.

Klecket

R.W.

Allain

J.P.

Wills

R.J.

McAfee

Fischl

Dubinsky

McNeely

M.C.

Mitsuya

Pluda

J.M.

Lawley

T.J.

Leuther

Safai

Collins

J.M.

Myers

C.E.

, and Broder

(1988) Phase I studies of 2′,3′-dideoxycyctidine in a severe human immunodeficiency virus infection as a single agent and alternating with zidovudine (AZT). Lancet 1: 76–80.

Inhibition of Feline Immunodeficiency Virus Production and HIV Tat Activity by Thiosemicarbazone Derivatives

Abstract

References