Disease relevance of S 1360

• OBJECTIVES: Study of HIV-1 resistance development to the diketo analogue S-1360, the first HIV-1 integrase strand transfer inhibitor that has entered clinical development [1].
• Compounds inhibiting HIV integrase, the third enzyme of HIV, are also available ultimately, with several such derivatives in clinical trials (L-731, 988 and S-1360) [2].

High impact information on S 1360

• Integrase-chimeric virus technology confirmed that the integrase mutations are indeed fully responsible for the resistance phenotype of IIIB/S-1360 [1].
• METHODS: The IIIB/S-1360(res) strains selected for 30, 50 and 70 passages in the presence of S-1360 were evaluated genotypically by sequencing analysis and phenotypically using the MT-4/MTT assay [1].
• Diketo acids such as S-1360 (1A) and L-731,988 (2) are potent and selective inhibitors of HIV-1 integrase (IN) [3].
• (ii) Other compounds have proceeded through preclinical and/or clinical development: CXCR4 antagonists (i.e. AMD070), CCR5 antagonists (i.e. SCH-C), NRTIs (such as amdoxovir), NNRTIs (such as etravirine), integrase inhibitors (such as S-1360) and PIs (such as tipranavir) [4].
• Third, IN has been validated as a legitimate target and the results from S-1360 (1) the only available IN inhibitor under clinical trials suggest synergistic effect with reverse transcriptase (RT) and protease (PR) inhibitors [5].

Biological context of S 1360

• We found that the conformation of S-1360 when bound in one of the active sites matches that of the experimentally observed results of IN escape mutants resistant to S-1360 [6].

Anatomical context of S 1360

• For these experiments, non-radiolabeled S-1360 was incubated with pooled human liver cytosol and NADPH in the presence of inhibitors, followed by quantitation of HP1 by LC/MS/MS [7].

Gene context of S 1360

• The cofactor dependence, subcellular location, and chemical inhibitor results implicated the aldo-keto reductase family of enzymes as the most likely pathway for generation of the major metabolite HP1 from S-1360 [7].

Analytical, diagnostic and therapeutic context of S 1360

• DESIGN: HIV-1(IIIB) was passaged in cell culture in the presence of increasing concentrations of S-1360 (IIIB/S-1360(res)) [1].
• Phenotypic cross-resistance to S-1360, a diketo analogue in clinical trials, was observed for all strains [8].

References