COMPARATIVE KINETIC ANALYSES OF INTERACTION OF INHIBITORS WITH RAUSCHER MURINE LEUKEMIA-VIRUS AND HUMAN-IMMUNODEFICIENCY-VIRUS REVERSE TRANSCRIPTASES

The inhibitory effects of several nucleoside triphosphate analogs on R auscher murine leukemia virus (RMuLV) and human immunodeficiency virus (HIV) type 1 reverse transcriptases (RTs) were studied. With RNA as t he template, the apparent K-m and apparent K-i values of HIV RT toward its substrates and inhibitors are 12 to 500 times lower than the corr esponding values for RMuLV RT. However, the K-i/K-m ratios (inhibition efficiencies) for HIV and RMuLV RTs are similar for AZTTP (zidovudine triphosphate), d4TTP ymidine-2'-ene-(3'-deoxy-2',3'-didehydrothymidin e) triphosphate], PMEADP [9-(2-phosphonylmethoxyethyl)adenine diphosph ate], FIAUTP uoro-2-deoxy-beta-D-arabinofuranosyl)-5-iodouracil tripho sphate], and HPMPCDP [(S)-1-(3-hydroxy-2-phosphylmethoxypropyl)cytosin e diphosphate]. With DNA as the template, the K-m values are similar f or HIV and RMuLV RTs. However, the K-i/K-m values of HIV and RMuLV RTs are significantly different for ddCTP, ddATP, and 3TCTP (2',3'-dideox y-3'-thiacytidine). The RTs of RMuLV and HIV are sufficiently differen t from one another that the kinetic inhibition constants for a particu lar antiviral compounds should be determined to indicate whether anti- RMuLV activity is likely to be predictive for the anti-HIV activity of the compound. This information, in conjunction with species-specific drug metabolism differences and tissue culture antiviral activity, is important in determining the suitability of a particular animal model.