A series of peptide derivatives based on the transition-state mimetic concept has been designed that inhibit the proteinase from the human immunodeficiency virus (HIV). The more active compounds inhibit both HIV-1 and HIV-2 proteinases in the nanomolar range with little effect at 10 micromolar against the structurally related human aspartic proteinases. Proteolytic cleavage of the HIV-1 gag polyprotein (p55) to the viral structural protein p24 was inhibited in chronically infected CEM cells. Antiviral activity was observed in the nanomolar range (with one compound active below 10 nanomolar) in three different cell systems, as assessed by p24 antigen and syncytium formation. Cytotoxicity was not detected at 10 and 5 micromolar in C8166 and JM cells, respectively, indicating a high therapeutic index for this new class of HIV proteinase inhibitors.

The response of patients infected with African subtypes of HIV-1 to HAART appears to be independent of regime, HIV-1 clade and baseline polymorphisms. Non-B subtypes are fully sensitive to HAART and, accordingly, therapy should not be withheld from African patients for reasons of viral diversity.

A series of monophosphate triester derivatives of 3′-azido-3′-deoxythymidine (AZT), designed as membrane-soluble pro-drugs of the nucleotide (AZTMP), have been tested for activity against the human immunodeficiency virus (HIV-1). It has been found that when carboxyl-protected, amino-linked amino acids, and alkyl chains, are asymmetrically substituted on the 5′-phosphate a significant antiviral effect is observed. Moreover, the activity of the compounds is profoundly dependent on the structure of the phosphate moiety, and in particular on the nature of the amino acid.

No abstract