The prolyl oligopeptidase inhibitor KYP‑2047 is not readily bioavailable to bloodstream form trypanosomes and human myelocytic leukemia cells

Authors

  • Chinenye Ajoko,

Keywords:

4‑phenylbutanoyl‑L‑prolyl‑2(S)‑cyanopyrrolidine, drug absorption, HL‑60 cells, prolyl endopeptidase, Trypanosoma brucei

Abstract

Introduction: Only three drugs are currently available for treatment of the neurological
stage of human African sleeping sickness caused by the protozoan parasite Trypanosoma
brucei. As these drugs have serious side effects and are difficult to administer, new and
safe antitrypanosomal medications are urgently required. Research in recent years has
shown that prolyl oligopeptidase (POP) inhibitors are promising trypanocidal agents.
As the novel POP inhibitor KYP‑2047 can cross the blood‑brain barrier, we aimed to
test whether this compound would prove to be a promising anti‑trypanosomal drug
candidate. Materials and Methods: The efficacy of KYP‑2047 to inhibit trypanosome
and human POP was evaluated with cell lysates using the fluorogenic peptide substrate
Suc‑Gly‑Pro‑Leu‑Gly‑Pro‑AMC. The trypanocidal and cytotoxic activity of KYP‑2047
was studied in vitro using bloodstream forms of T. brucei and human myelocytic
leukemia HL‑60 cells. The bioavailability of KYP‑2047 to T. brucei and HL‑60 cells was
determined by incubation of cells with the inhibitor for 24 h, followed by measuring the
residual POP activity. Results: KYP‑2047 inactivated POP in cell lysates of T. brucei and
HL‑60 cells with IC50 values in the mid nanomolar range indicating that the compound
is a very potent inhibitor of the trypanosome and human enzyme. However, KYP‑2047
did not affect the growth of T. brucei and HL‑60 cells. Upon incubation of the cells
with 100 μM KYP‑2047, POP activity was inhibited between 20% and 80% which is
too low to have any effect on cell growth. Conclusion: The absence of trypanocidal
and cytotoxic activity of KYP‑2047 is due to low bioavailability of the inhibitor to
bloodstream forms of T. brucei and human HL‑60 cells.

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Published

2015-01-28

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Articles

How to Cite

The prolyl oligopeptidase inhibitor KYP‑2047 is not readily bioavailable to bloodstream form trypanosomes and human myelocytic leukemia cells. (2015). Journal of Pharmaceutical Negative Results, 6(1), 7-10. https://pnrjournal.com/index.php/home/article/view/84