title: Oligopeptide cyclophilin inhibitors: a reassessment.
abstract: Potent cyclophilin A (CypA) inhibitors such as non-immunosuppressive cyclosporin A (CsA) derivatives have been already used in clinical trials in patients with viral infections. CypA is a peptidyl prolyl cis/trans isomerase (PPIase) that catalyzes slow prolyl bond cis/trans interconversions of the backbone of substrate peptides and proteins. In this study we investigate whether the notoriously low affinity inhibitory interaction of linear proline-containing peptides with the active site of CypA can be increased through a combination of a high cis/trans ratio and a negatively charged C-terminus as has been recently reported for Trp-Gly-Pro. Surprisingly, isothermal titration calorimetry did not reveal formation of an inhibitory CypA/Trp-Gly-Pro complex previously described within a complex stability range similar to CsA, a nanomolar CypA inhibitor. Moreover, despite of cis content of 41% at pH 7.5 Trp-Gly-Pro cannot inhibit CypA-catalyzed standard substrate isomerization up to high micromolar concentrations. However, in the context of the CsA framework a net charge of -7 clustered at the amino acid side chain of position 1 resulted in slightly improved CypA inhibition.
authors.affiliation: Max Planck Research Unit for Enzymology of Protein Folding, Weinbergweg 22, D-06120 Halle/Saale, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schumann
authors.forename: Günther
authors.initials: G
authors.lastname: Jahreis
authors.forename: Viktoria
authors.initials: V
authors.lastname: Kahlert
authors.forename: Christian
authors.initials: C
authors.lastname: Lücke
authors.forename: Gunter
authors.initials: G
authors.lastname: Fischer
mesh_terms: D002151:Calorimetry; D020134:Catalytic Domain; D021984:Cyclophilin A / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011392:Proline / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: D004791:Enzyme Inhibitors; D009842:Oligopeptides; D011392:Proline; D021984:Cyclophilin A