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

摘要: Abstract Trypanothione reductase (TryR) is a well-established target in the search for novel antitrypanosomal and antileishmanial agents. We have previously identified linear lactam-bridged 13-residue peptides derived from an α-helical region making up part of dimeric interface Leishmania infantum TryR (Li-TryR) which prevent trypanothione reduction by disrupting enzyme dimerization. now show that i,i + 4 side-chain cross-linking with all-hydrocarbon staple stabilizes helical structure these significantly improves their resistance to protease cleavage relative previous cyclic lactam analogues. Interestingly, replacement amide bridge hydrocarbon at same cyclization positions generates derivatives (2 3) similarly inhibit oxidoreductase activity but unexpectedly stabilize homodimer. The most proteolytically stable peptide 2 covalently linked oligoarginines displayed potent in vitro leishmanicidal against L. infantum parasites.