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Title

Trypanothione reductase inhibition and anti-leishmanial activity of all-hydrocarbon stapled α-helical peptides with improved proteolytic stability

AuthorsRuiz-Santaquiteria, Marta ; Castro, Sonia de ; Toro, Miguel A.; Lucio, Héctor de; Gutiérrez, Kilian Jesús; Sánchez-Murcia, Pedro A. ; Jiménez, M. Angeles ; Gago, Federico ; Jiménez-Ruiz, Antonio; Camarasa Rius, María José ; Velázquez, Sonsoles
KeywordsStapled peptides
Leishmania infantum
Cell-penetrating peptides
Trypanothione reductase
Protein-protein interactions
Issue Date2018
PublisherElsevier
CitationEuropean Journal of Medicinal Chemistry 149: 238-247 (2018)
AbstractTrypanothione reductase (TryR) is a well-established target in the search for novel antitrypanosomal and antileishmanial agents. We have previously identified linear and lactam-bridged 13-residue peptides derived from an α-helical region making up part of the dimeric interface of Leishmania infantum TryR (Li-TryR) which prevent trypanothione reduction by disrupting enzyme dimerization. We now show that i,i + 4 side-chain cross-linking with an all-hydrocarbon staple stabilizes the helical structure of these peptides and significantly improves their resistance to protease cleavage relative to previous linear and cyclic lactam analogues. Interestingly, replacement of the amide bridge by the hydrocarbon staple at the same cyclization positions generates derivatives (2 and 3) that similarly inhibit oxidoreductase activity of the enzyme but unexpectedly stabilize the TryR homodimer. The most proteolytically stable peptide 2 covalently linked to oligoarginines displayed potent in vitro leishmanicidal activity against L. infantum parasites.
Publisher version (URL)http://dx.doi.org/10.1016/j.ejmech.2018.02.071
URIhttp://hdl.handle.net/10261/166587
DOIhttp://dx.doi.org/10.1016/j.ejmech.2018.02.071
Identifiersdoi: 10.1016/j.ejmech.2018.02.071
issn: 0223-5234
e-issn: 1768-3254
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