Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.
Development of new potent and selective agents against HIV (human immunodeficiency virus).
Verh K Acad Geneeskd Belg. 1991;53(6):629-55. Unique Identifier : AIDSLINE MED/92280287 Pauwels R; Schols D; Rega Institute for Medical Research, Leuven, Belgium.
Abstract:
The human immunodeficiency virus (HIV) is a lentivirus which replicates within critical cells of the immune system, particularly CD4+ T-cells and monocyte/macrophages, leading to a progressive loss of helper T-cells and profound immunosuppression. This condition is known as the acquired immunodeficiency syndrome (AIDS). A rational screening strategy was adopted to evaluate new anti-HIV agents. Primary in vitro evaluation of antiviral compounds and studies of the relationship between structure and antiviral activity were carried out in a CD4+ T-cell line (MT-4). These cells develop a cytopathic effect (CPE) within a few days after infection. Initially, protection against the HIV-induced cytopathic effect as well as the MT-4 host cell cytotoxicity was determined by a highly automated evaluation system. Promising lead compounds emerging from these studies were then further investigated for their anti-HIV properties in other target cells and against different HIV-1 and HIV-2 strains. This strategy allowed the identification of several potent and selective inhibitors of HIV replication in vitro. Following the 3'-azidothymidine (AZT) lead, we synthesized and evaluated other 2',3'-dideoxynucleoside analogues with modifications in the base and/or sugar moiety. Based on their selectivity indexes in vitro, several congeners of this group, including 2',3'-thymidine (ddeThd, D4T) and 5-chloro-3'-fluoro-2',3'-dideoxyuridine (FddClUrd), seem at least as promising as AZT. From a series of phosphonylmethoxyalkylpurines and -pyrimidines, 9-(2-phosphonylmethoxyethyl)adenine (PMEA) and 9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine (PMEDAP) emerged as a new class of broad-spectrum anti-retrovirus agents. Sulfated polysaccharides and sulfated polymers represent another class of compounds achieving high therapeutic indexes in vitro. Comparative studies allowed to define the structural requirements for anti-HIV activity. Finally, a rational screening strategy allowed the identification of tetrahydro-imidazo[4,5,1-jk][1,4]-benzodiazepine-2(1H)-one and thione (TIBO) derivatives which represent a complete new class of anti-HIV-1 agents.(ABSTRACT TRUNCATED AT 400 WORDS)
Keywords: Antiviral Agents/*ISOLATION & PURIF/THERAPEUTIC USE Automation Dideoxynucleosides/ISOLATION & PURIF *Drug Design Human HIV/*DRUG EFFECTS/PATHOGENICITY HIV Infections/DRUG THERAPY Support, Non-U.S. Gov't Virus Replication/DRUG EFFECTS JOURNAL ARTICLE 920930
M9290876
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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.
