Inactivation of murine leukemia virus by compounds that react with the zinc finger in the viral nucleocapsid protein.
All retroviral nucleocapsid (NC) proteins, except those of spumaretroviruses, contain one or two copies of the conserved sequence motif C-X2-C-X4-H-X4-C. The conserved cysteine and histidine residues coordinate a zinc ion in each such motif. Rice et al. (W. G. Rice, J. G. Supko, L. Malspeis, R. W. Buckheit, Jr., D. Clanton, M. Bu, L. Graham, C. A. Schaeffer, J. A. Turpin, J. Domagala, R. Gogliotti, J. P. Bader, S. M. Halliday, L. Coren, R. C. Sowder II, L. 0. Arthur, and L. E. Henderson, Science 270:1194-1197, 1995) have described a series of compounds which inactivate human immunodeficiency virus type 1 (HIV-1) particles and oxidize the cysteine thiolates in the NC zinc finger. We have characterized the effects of three such compounds on Moloney murine leukemia virus (MuLV). We find that, as with HIV-1, the compounds inactivate cell-free MuLV particles and induce disulfide cross-linking of NC in these particles. The killed MuLV particles were found to be incapable of synthesizing full-length viral DNA upon infection of a new host cell. When MuLV particles are synthesized in the presence of one of these compounds, the normal maturational cleavage of the Gag polyprotein does not occur. The compounds have no effect on the infectivity of human foamy virus, a spumaretrovirus lacking zinc fingers in its NC protein. The resistance of foamy virus supports the hypothesis that the zinc fingers are the targets for inactivation of MuLV and HIV- I by the compounds. The absolute conservation of the zinc finger motif among oncoretroviruses and lentiviruses and the lethality of all known mutations altering the zinc-binding residues suggest that only the normal, wild-type structure can efficiently perform all of its functions. This possibility would make the zinc finger an ideal target for antiretroviral agents.
Rein
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A
Retroviral Genetics Section, ABL-Basic Research Program, SAIC-Frederick, National Cancer Institute, Frederick Cancer Research and Development Center, Maryland 21702-1201, USA.
Ott
D E
DE
Mirro
J
J
Arthur
L O
LO
Rice
W
W
Henderson
L E
LE
D016475:3T3 Cells; D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D002213:Capsid / Q000378:metabolism*; D006801:Humans; D009052:Leukemia Virus, Murine / Q000187:drug effects / Q000378:metabolism*; D007942:Leukemia, Experimental / Q000188:drug therapy / Q000821:virology*; D051379:Mice; D012192:Retroviridae Infections / Q000188:drug therapy / Q000821:virology*; D014412:Tumor Virus Infections / Q000188:drug therapy / Q000821:virology*; D016335:Zinc Fingers / Q000187:drug effects*
D000998:Antiviral Agents