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Characterization of P. falciparum dipeptidyl aminopeptidase 3 specificity identifies differences in amino acid preferences between peptide‐based substrates and covalent inhibitors
Author(s) -
Vries Laura E.,
Sanchez Mateo I.,
Groborz Katarzyna,
Kuppens Laurie,
Poreba Marcin,
Lehmann Christine,
Nevins Neysa,
WithersMartinez Chrislaine,
Hirst David J.,
Yuan Fang,
ArastuKapur Shirin,
Horn Martin,
Mares Michael,
Bogyo Matthew,
Drag Marcin,
Deu Edgar
Publication year - 2019
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.14953
Subject(s) - proteases , aminopeptidase , biochemistry , peptide , protease , cysteine , enzyme , biology , amino acid , cysteine protease , chemistry , leucine
Malarial dipeptidyl aminopeptidases ( DPAP s) 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 DPAP s and CatC, and used this information to develop highly selective DPAP 1 and DPAP 3 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 DPAP 1, DPAP 3, and CatC, and between substrates and inhibitors in the case of DPAP 3. 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.