Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.
HUMAN RETROVIRUS PROTEASES AS TARGETS FOR THERAPY (MEETING ABSTRACT)
Seventh International Symposium on Cancer Research of the House of the Hungarian Academy of Sciences: Convergences of International Cancer Research. June 12-14, 1991, Budapest, Hungary, p. 15, 1991.. Unique Identifier : AIDSLINE ICDB/92679644 Oroszlan S; United States
Abstract:
The discovery in the early 1980s of human retroviruses, human T-cell leukemia virus (HTLV) and human immunodeficiency virus (HIV), the etiologic agent of adult T-cell leukemia and AIDS, respectively, has brought serious challenges to public health. Worldwide, major efforts are being directed towards controlling virus infection in order to stop the development and progression of the disease. Chemotherapy is an attractive approach. Inhibitors of the viral replication enzyme, reverse transcriptase are already in clinical use. The virally encoded protease (PR), also, has an essential role in virus replication. Therefore, the PR is also a potential target for chemotherapy. This enzyme has been known to be responsible for the processing of the Gag and Gag-Pol precursor-polyproteins that are the primary translational products of HTLV and HIV genome-size mRNA and assemble with genomic RNA to form the noninfectious immature virus. To produce mature infectious virus, the processing of the polyproteins into the functional structural proteins and enzymes is necessary. The PR itself is synthesized by ribosomal frameshifting as a part of the proteolytically inactive Gag-Pro and/or Gag-Pro-Pol fusion proteins and is activated in the extracellular immature particles. The active dimer has an aspartic proteinase-like folding and active site. In addition to the maturation cleavages which have been extensively studied, we have recently found and characterized another action of the PR: the in situ cleavage of the nucleocapsid (NC) protein of the mature viral capsid. This suggests a previously unrecognized role of PR in the early phase of infection, ie, reverse transcription-integration. It is conceivable that the cleavage of the NC protein by the PR is required to initiate synthesis of viral DNA. The dual action of the PR makes it one of the most attractive targets for drug therapy and suggests that inhibitors of PR may be useful not only for therapy, but also for prevention of virus infection. PR inhibitors are effective in both newly infected, and chronically infected cells and may have an advantage over inhibitors of the other viral enzymes. Studies with various PR inhibitors both in vitro and in vivo (cell culture) are discussed. (5 Refs)
Keywords: Capsid/GENETICS Genes, gag/GENETICS Genes, pol/GENETICS Genome, Viral HIV/GENETICS Protease Inhibitors/PHARMACOLOGY Retroviridae Infections/DRUG THERAPY/ENZYMOLOGY/*GENETICS RNA-Directed DNA Polymerase/GENETICS RNA, Messenger/GENETICS Viral Fusion Proteins/GENETICS *Virus Replication ABSTRACT
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Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.
