Aminosugar derivatives as potential anti-human immunodeficiency virus agents.
Recent data suggest that aminosugar derivatives which inhibit glycoprotein processing have potential anti-human immunodeficiency virus (HIV) activity. These inhibitory effects may be due to disruption of cell fusion and subsequent cell-cell transmission of the acquired immunodeficiency syndrome (AIDS) virus. Free virus particles able to bind CD4-positive cells are still produced in the presence of these compounds with only partial reduction of infectivity. We now report a method to score in parallel both the degree of antiviral activity and the effect on cell division of aminosugar derivatives. We find that (i) the compounds 1,4-dideoxy-1,4-imino-L-arabinitol and N-(5-carboxymethyl-1-pentyl)-1,5-imino-L-fucitol partially inhibit the cytopathic effect (giant cell formation, etc.) of HIV and yield of infectious virus; (ii) the compounds N-methyldeoxynojirimycin and N-ethyldeoxynojirimycin reduce the yield of infectious HIV by an order of four and three logarithms, respectively; and (iii) one compound, N-butyldeoxynojirimycin, of the 47 compounds previously screened reduces infectious viral particles by a logarithmic order greater than five at noncytotoxic concentrations. In addition, long-term growth of infected cells in the presence of N-butyldeoxynojirimycin gradually decreases the proportion of infected cells, leading to eventual elimination of HIV from culture. This result suggests that replication is associated with cytolysis. The ability to break the cycle of replication and reinfection has important implications in the chemotherapy of AIDS.
Karpas
A
A
Clinical School, Department of Hematological Medicine, University of Cambridge, United Kingdom.
Fleet
G W
GW
Dwek
R A
RA
Petursson
S
S
Namgoong
S K
SK
Ramsden
N G
NG
Jacob
G S
GS
Rademacher
T W
TW
D000606:Amino Sugars / Q000494:pharmacology*; D000998:Antiviral Agents; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D015497:HIV-1 / Q000187:drug effects*; D015498:HIV-2 / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes
D000606:Amino Sugars; D000998:Antiviral Agents