Sch44342

158,000

(250)c

(>114,000)c

a In vitro inhibition studies with FTase and GGTase I inhibitors were carried out with T. brucei and rat FTase using 5 pM RAS-CVIM and 0.75pM [3H]FPP for FTase or using 5 pM H-Ras-CVLL and 1 pM [3H]GGPP as substrates for GGTase I. b Estimated error for all IC50s is <20%.

c Values in parentheses are previously reported IC50 values for L-745,631 (28) and for FTI-276 and GGTI-297 (29) (using H-Ras-CVLS and H-Ras-CVLL as substrates for human FTase and GGTase I, respectively), and for SCH-44342 using H-Ras-CVLS and H-Ras-CVLL as substrates and rat FTase and GGTase I, respectively (30).

a In vitro inhibition studies with FTase and GGTase I inhibitors were carried out with T. brucei and rat FTase using 5 pM RAS-CVIM and 0.75pM [3H]FPP for FTase or using 5 pM H-Ras-CVLL and 1 pM [3H]GGPP as substrates for GGTase I. b Estimated error for all IC50s is <20%.

c Values in parentheses are previously reported IC50 values for L-745,631 (28) and for FTI-276 and GGTI-297 (29) (using H-Ras-CVLS and H-Ras-CVLL as substrates for human FTase and GGTase I, respectively), and for SCH-44342 using H-Ras-CVLS and H-Ras-CVLL as substrates and rat FTase and GGTase I, respectively (30).

produced a stronger effect than did GGTI-298, which is consistent with its higher potency on T. brucei FTase activity in vitro and on cell growth. Radiolabeling of the prominent bands in the 28-35 kDa region was not significantly affected by these inhibitors. At least some of these proteins may be Rab proteins, which are present in trypanosomatids, do not contain CAAX sequences and are most likely doubly geranylgeranylated by GGTase II. CAAX mimetics are not expected to inhibit parasite GGTase II because the mammalian form of this enzyme does not recognize short peptides (9).

Table 2

Inhibition of T. brucei and T. cruzi Growth by CAAX Mimetics"

Table 2

Inhibition of T. brucei and T. cruzi Growth by CAAX Mimetics"

Inhibitor

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