Peptidomimetic nitrile inhibitors of malarial protease falcipain-2 with high selectivity against human cathepsins

[Display omitted] Falcipain-2 (FP2) is an essential enzyme in the lifecycle of malaria parasites such as Plasmodium falciparum, and its inhibition is viewed as an attractive mechanism of action for new anti-malarial agents. Selective inhibition of FP2 with respect to a family of human cysteine prote...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2018-05, Vol.28 (9), p.1540-1544
Main Authors: Nizi, Emanuela, Sferrazza, Alessio, Fabbrini, Danilo, Nardi, Valentina, Andreini, Matteo, Graziani, Rita, Gennari, Nadia, Bresciani, Alberto, Paonessa, Giacomo, Harper, Steven
Format: Article
Language:English
Subjects:
3-Pyridine
Antimalarials - chemical synthesis
Antimalarials - chemistry
Antimalarials - pharmacology
Cathepsins - antagonists & inhibitors
Cathepsins - metabolism
Cysteine Endopeptidases - metabolism
Cysteine Proteinase Inhibitors - chemical synthesis
Cysteine Proteinase Inhibitors - chemistry
Cysteine Proteinase Inhibitors - pharmacology
Dose-Response Relationship, Drug
Falcipain-2 Peptidomimetic-nitrile
Humans
Malaria
Malaria, Falciparum - drug therapy
Malaria, Falciparum - metabolism
Molecular Structure
Nitriles - chemical synthesis
Nitriles - chemistry
Nitriles - pharmacology
Peptidomimetics - chemical synthesis
Peptidomimetics - chemistry
Peptidomimetics - pharmacology
Selective
Structure-Activity Relationship
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Summary:[Display omitted] Falcipain-2 (FP2) is an essential enzyme in the lifecycle of malaria parasites such as Plasmodium falciparum, and its inhibition is viewed as an attractive mechanism of action for new anti-malarial agents. Selective inhibition of FP2 with respect to a family of human cysteine proteases (that include cathepsins B, K, L and S) is likely to be required for the development of agents targeting FP2. Here we describe a series of P2-modified aminonitrile based inhibitors of FP2 that provide a clear strategy toward addressing selectivity for the P. falciparum and show that it can provide potent FP2 inhibitors with strong selectivity against all four of these human cathepsin isoforms.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2018.03.069