The Plasmodium falciparum cysteine peptidases FP-2 (falcipain-2) and FP-3 (falcipain-3), members of the papain-like CAC1 family, are essential haemoglobinases and are therefore potential anti-malarial drug targets. To facilitate a rational drug discovery programme, in the current study we analysed the synthetic substrate and model inhibitor profiles of FP-2 and FP-3 as well as BP-2 (berghepain-2), an orthologue from the rodent parasite Plasmodium berghei. With respect to substrate catalysis, FP-2 exhibited a promiscuous substrate profile based around a consensus non-primeside motif, FP-3 was somewhat more restricted and BP-2 was comparatively specific. Substrate turnover for FP-2 was driven by a basic or acidic P1 residue, whereas for FP-3 turnover occurred predominately through a basic P1 residue only, and for BP-2, turnover was again mainly through a basic P1 residue for some motifs and surprisingly a glycine in the P1 position for other motifs. Within these P1 binding elements, additional recognition motifs were observed with subtle nuances that switched substrate turnover on or off through specific synergistic combinations. The peptidases were also profiled against reversible and irreversible cysteine peptidase inhibitors. The results re-iterated the contrasting kinetic behaviour of each peptidase as observed through the substrate screens. The results showed that the substrate and inhibitor preferences of BP-2 were markedly different from those of FP-2 and FP-3. When FP-2 and FP-3 were compared to each other they also displayed similarities and some significant differences. In conclusion, the in vitro data highlights the current difficulties faced by a peptidase directed anti-malarial medicinal chemistry programme where compounds need to be identified with potent activity against at least three peptidases, each of which displays distinct biochemical traits.
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October 2006
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Research Article|
September 13 2006
Substrate mapping and inhibitor profiling of falcipain-2, falcipain-3 and berghepain-2: implications for peptidase anti-malarial drug discovery
Manoj K. Ramjee;
Manoj K. Ramjee
1
1Amura Therapeutics Limited, Horizon Park, Barton Road, Comberton, CB3 7AJ, U.K.
1To whom correspondence should be addressed (email manoj.ramjee@amura.co.uk).
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Nicholas S. Flinn;
Nicholas S. Flinn
1Amura Therapeutics Limited, Horizon Park, Barton Road, Comberton, CB3 7AJ, U.K.
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Tracy P. Pemberton;
Tracy P. Pemberton
1Amura Therapeutics Limited, Horizon Park, Barton Road, Comberton, CB3 7AJ, U.K.
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Martin Quibell;
Martin Quibell
1Amura Therapeutics Limited, Horizon Park, Barton Road, Comberton, CB3 7AJ, U.K.
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Yikang Wang;
Yikang Wang
1Amura Therapeutics Limited, Horizon Park, Barton Road, Comberton, CB3 7AJ, U.K.
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John P. Watts
John P. Watts
1Amura Therapeutics Limited, Horizon Park, Barton Road, Comberton, CB3 7AJ, U.K.
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Publisher: Portland Press Ltd
Received:
March 20 2006
Revision Received:
June 07 2006
Accepted:
June 15 2006
Accepted Manuscript online:
June 15 2006
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2006
Biochem J (2006) 399 (1): 47–57.
Article history
Received:
March 20 2006
Revision Received:
June 07 2006
Accepted:
June 15 2006
Accepted Manuscript online:
June 15 2006
Citation
Manoj K. Ramjee, Nicholas S. Flinn, Tracy P. Pemberton, Martin Quibell, Yikang Wang, John P. Watts; Substrate mapping and inhibitor profiling of falcipain-2, falcipain-3 and berghepain-2: implications for peptidase anti-malarial drug discovery. Biochem J 1 October 2006; 399 (1): 47–57. doi: https://doi.org/10.1042/BJ20060422
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