Suppression of retrovirial replication: inactivation of murine leukemia virus by compounds reacting with the zinc finger in the viral nucleocapsid protein.
All retroviral nucleocapsid (NC) proteins, except those of spumaretroviruses, contain one or two zinc fingers, consisting of the sequence C-X2-C-X4-H-X4-C. Rice et al. (Science 270:1194-1197, 1995) have described a series of compounds which inactivate HIV-1 particles and oxidize the sulfur atoms 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. In contrast, 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-1 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
A
A
Retroviral Genetics Section, SAIC-Frederick, NCI-Frederick Cancer Research and Development Center, MD 21702-1201, USA.
Ott
D E
DE
Mirro
J
J
Arthur
L O
LO
Rice
W G
WG
Henderson
L E
LE
D000595:Amino Acid Sequence; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D003432:Cross-Linking Reagents / Q000494:pharmacology*; D004220:Disulfides; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D051379:Mice; D008979:Moloney murine leukemia virus / Q000187:drug effects / Q000502:physiology*; D016296:Mutagenesis; D019251:Nucleocapsid / Q000737:chemistry* / Q000187:drug effects; D016092:Spumavirus / Q000502:physiology*; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology*; D016335:Zinc Fingers
D000998:Antiviral Agents; D003432:Cross-Linking Reagents; D004220:Disulfides