Advertisment ACS-IndiaSymposium
 
Journal of Pharmaceutical Negative Results
  Print this page Email this page Small font sizeDefault font sizeIncrease font size 
Search Article 
  
Advanced search 
 Home | About us | Editorial board | Search | Ahead of print | Current issue | Archives | Submit article | Instructions | Subscribe | Contacts  
 
ORIGINAL ARTICLE
Year : 2015  |  Volume : 6  |  Issue : 1  |  Page : 7-10

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


BioMedical Research Centre, Department of Medicine, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, United Kingdom

Correspondence Address:
Dr. Dietmar Steverding
BioMedical Research Centre, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ
United Kingdom
Login to access the Email id

Source of Support: This work was supported by the John & Pamela Salter Charitable Trust (R22465)., Conflict of Interest: None


DOI: 10.4103/0976-9234.157376

Rights and Permissions

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 IC 50 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.


[FULL TEXT] [PDF]*
Print this article     Email this article
 Next article
 Previous article
 Table of Contents

 Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
 Citation Manager
 Access Statistics
 Reader Comments
 Email Alert *
 Add to My List *
 * Requires registration (Free)
 

 Article Access Statistics
    Viewed3754    
    Printed138    
    Emailed0    
    PDF Downloaded1038    
    Comments [Add]    

Recommend this journal