Peptidomimetic nitrile inhibitors of malarial protease falcipain-2 with high selectivity against human cathepsins. Issue 9 (15th May 2018)

• Record Type: Journal Article
• Authors: Nizi, Emanuela; Sferrazza, Alessio; Fabbrini, Danilo; Nardi, Valentina; Andreini, Matteo; Graziani, Rita; Gennari, Nadia; Bresciani, Alberto; Paonessa, Giacomo; Harper, Steven
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 9(2018)
• Page Start: 1540
• Page End: 1544
• Publication Date: 2018-05-15
• Subjects: Malaria -- Falcipain-2 Peptidomimetic-nitrile -- 3-Pyridine -- Selective; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.03.069
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: 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 P 2-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.