Journal
FEBS JOURNAL
Volume 286, Issue 20, Pages 3998-4023Publisher
WILEY
DOI: 10.1111/febs.14953
Keywords
dipeptidyl aminopeptidase; malaria; positional scanning; proteases; specificity
Categories
Funding
- Cancer Research UK [FC001043] Funding Source: Medline
- Erasmus Funding Source: Medline
- European Regional Development Fund [RVO 61388963] Funding Source: Medline
- Medical Research Council [FC001043] Funding Source: Medline
- Royal Society [SHDF 099950] Funding Source: Medline
- Wellcome Trust [SHDF 099950, FC001043] Funding Source: Medline
- ChemBioDrug [CZ.02.1.01/0.0/16_019/0000729] Funding Source: Medline
Ask authors/readers for more resources
Malarial dipeptidyl aminopeptidases (DPAPs) are cysteine proteases important for parasite development thus making them attractive drug targets. In order to develop inhibitors specific to the parasite enzymes, it is necessary to map the determinants of substrate specificity of the parasite enzymes and its mammalian homologue cathepsin C (CatC). Here, we screened peptide-based libraries of substrates and covalent inhibitors to characterize the differences in specificity between parasite DPAPs and CatC, and used this information to develop highly selective DPAP1 and DPAP3 inhibitors. Interestingly, while the primary amino acid specificity of a protease is often used to develop potent inhibitors, we show that equally potent and highly specific inhibitors can be developed based on the sequences of nonoptimal peptide substrates. Finally, our homology modelling and docking studies provide potential structural explanations of the differences in specificity between DPAP1, DPAP3, and CatC, and between substrates and inhibitors in the case of DPAP3. Overall, this study illustrates that focusing the development of protease inhibitors solely on substrate specificity might overlook important structural features that can be exploited to develop highly potent and selective compounds.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available