Characterization of P. falciparum dipeptidyl aminopeptidase 3 specificity identifies differences in amino acid preferences between peptide-based substrates and covalent inhibitors

Autor: Marcin Drag, Fang Yuan, Katarzyna Groborz, Martin Horn, Edgar Deu, Chrislaine Withers-Martinez, Laurie Kuppens, Neysa Nevins, Shirin Arastu-Kapur, Matthew Bogyo, Michael Mareš, Mateo I. Sánchez, Christine Lehmann, David Jonathan Hirst, Marcin Poreba, Laura E. de Vries
Rok vydání: 2019
Předmět:
Models
Molecular
0301 basic medicine
Proteases
Erythrocytes
Protein Conformation
medicine.medical_treatment
Plasmodium falciparum
malaria
lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4]
specificity
Peptide
Biochemistry
Aminopeptidase
Substrate Specificity
Cathepsin C
03 medical and health sciences
0302 clinical medicine
All institutes and research themes of the Radboud University Medical Center
positional scanning
medicine
Humans
Protease Inhibitors
Amino Acids
Malaria
Falciparum
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
Molecular Biology
chemistry.chemical_classification
Protease
Molecular Structure
Chemistry
Original Articles
Cell Biology
Peptide Fragments
3. Good health
Amino acid
030104 developmental biology
Enzyme
Docking (molecular)
030220 oncology & carcinogenesis
Original Article
proteases
dipeptidyl aminopeptidase
Zdroj: FEBS Journal, 286, 20, pp. 3998-4023
The Febs Journal
FEBS Journal, 286, 3998-4023
ISSN: 1742-464X
Popis: 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.
We have used peptide‐based libraries of substrates and covalent inhibitors to characterize the specificity of Plasmodium dipeptidyl aminopeptidase 3, a protease important for red blood cell invasion. Interestingly, we observed significant differences in amino acid preference between substrates and inhibitors, and showed that highly potent and specific inhibitors can be developed based on the sequences of nonoptimal peptide substrates.
Databáze: OpenAIRE
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