title: Development of new potent and selective agents against HIV (human immunodeficiency virus).
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)
authors.affiliation: Rega Institute for Medical Research, Leuven, Belgium.
authors.forename: R
authors.initials: R
authors.lastname: Pauwels
authors.forename: D
authors.initials: D
authors.lastname: Schols
mesh_terms: D000998:Antiviral Agents / Q000302:isolation & purification* / Q000627:therapeutic use; D001331:Automation; D015224:Dideoxynucleosides / Q000302:isolation & purification; D015195:Drug Design; D006678:HIV / Q000187:drug effects* / Q000472:pathogenicity; D015658:HIV Infections / Q000188:drug therapy; D006801:Humans; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D015224:Dideoxynucleosides