Inhibition of Friend virus replication by a compound that reacts with the nucleocapsid zinc finger: anti-retroviral effect demonstrated in vivo.
The zinc finger structure that is found in the nucleocapsid protein of nearly all retroviruses has been proposed as a target for antiviral therapy. Since compounds that chemically attack the cysteines of the finger have been shown to inactivate both human immunodeficiency virus type 1 (HIV-1) and murine leukemia virus (MuLV) in vitro, 14 of these compounds were tested in an MuLV-induced Friend disease model to assess their ability to inhibit retroviral replication in vivo. Of the 14 compounds tested, only Aldrithiol-2 clearly exhibited anti-retroviral activity as measured indirectly by the delay of Friend disease onset (P < 0.05). These results were confirmed by quantitative competitive polymerase chain reaction studies which monitored viral spread by measuring the level of viral DNA in the peripheral blood mononuclear cells of treated mice. Comparison of treated mice with untreated mice revealed that Aldrithiol-2 produced a greater than 2-log reduction in virus levels. These results functionally demonstrate that a zinc finger-attacking compound can inhibit viral replication in vivo. Since only 1 of the 14 compounds studied was effective, this study also shows the importance of in vivo testing of these types of antiviral compounds in an animal model. Given the strict conservation of the metal-coordinating cysteine structure within HIV-1 and MuLV zinc fingers, our results support the proposal that anti-retroviral drugs which target the nucleocapsid zinc finger may be clinically useful against HIV-1.
Ott
D E
DE
AIDS Vaccine Program, SAIC/Frederick, National Cancer Institute, Maryland 21702-1201, USA. ott@avpvx1.ncifcrf.gov
Hewes
S M
SM
Alvord
W G
WG
Henderson
L E
LE
Arthur
L O
LO
D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology*; D052160:Benzothiazoles; D003627:Data Interpretation, Statistical; D005622:Friend murine leukemia virus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D007942:Leukemia, Experimental / Q000188:drug therapy* / Q000821:virology; D051379:Mice; D019251:Nucleocapsid / Q000187:drug effects*; D012192:Retroviridae Infections / Q000188:drug therapy* / Q000821:virology; D012191:Retroviridae Proteins / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology*; D014412:Tumor Virus Infections / Q000188:drug therapy* / Q000821:virology; D014779:Virus Replication / Q000187:drug effects*; D016335:Zinc Fingers
D000998:Antiviral Agents; D052160:Benzothiazoles; D012191:Retroviridae Proteins; D013844:Thiazoles; C028000:dibenzothiazyl disulfide