Please use this identifier to cite or link to this item: https://doi.org/10.1016/j.bbrc.2005.07.147
Title: Characterization of amino acid variation at strategic positions in parasite and human proteases for selective inhibition of falcipains in Plasmodium falciparum
Authors: Liuh, L.G.
Sim, T.S. 
Keywords: Biochemical characterization
Falcipain
Homology modeling
Rational drug design
Site-directed mutagenesis
Issue Date: 2005
Source: Liuh, L.G., Sim, T.S. (2005). Characterization of amino acid variation at strategic positions in parasite and human proteases for selective inhibition of falcipains in Plasmodium falciparum. Biochemical and Biophysical Research Communications 335 (3) : 762-770. ScholarBank@NUS Repository. https://doi.org/10.1016/j.bbrc.2005.07.147
Abstract: Falcipains (FP) of Plasmodium falciparum are important virulence factors marked as potential targets for antimalarial drug discovery. In this study, the previously uncharacterized fp2B (PF11_0161) was shown to be highly expressed as an active enzyme during the erythrocytic stage. With three related proteases in the FP family and the existence of human homologues, it is prudent to identify clusters of residues unique to the parasite proteases that can be targeted selectively for drug design. Using bioinformatic tools, we have carefully mapped out a highly conserved and unique region constituted by I85, S149, and A151 in the plasmodial proteases that can influence the development of compounds capable of inhibiting the entire FP family. Taking drug interactions with the human homologues into consideration, these residues in FP2B were replaced with the cognate residues found in human cathepsin L (catL) for evaluation. Despite the high sequence similarity between the FP2 isozymes (97.5%), FP2B is found to be more tolerant to amino acid substitution at position 149 than FP2A. This structural disparity implied that residues mediating peptide substrate interactions are not fully conserved across the FP family and warrant attention in the design and evaluation of protease inhibitors focused on the FPs. The simultaneous substitution of the neighboring residues (I85 or A151) rendered the double mutants (S149A/I85M and S149A/A151D) completely inactive. Significantly, the mutations did not result in 'catL-like' specificity, suggesting that substrate-based inhibitors could be rationally designed against these important parasite-specific structural determinants. © 2005 Elsevier Inc. All rights reserved.
Source Title: Biochemical and Biophysical Research Communications
URI: http://scholarbank.nus.edu.sg/handle/10635/24711
ISSN: 0006291X
DOI: 10.1016/j.bbrc.2005.07.147
Appears in Collections:Staff Publications

Show full item record
Files in This Item:
There are no files associated with this item.

SCOPUSTM   
Citations

8
checked on Dec 7, 2017

WEB OF SCIENCETM
Citations

9
checked on Nov 22, 2017

Page view(s)

128
checked on Dec 11, 2017

Google ScholarTM

Check

Altmetric


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.