Oligopeptide cyclophilin inhibitors: a reassessment.

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Schumann M, Jahreis G, Kahlert V, Lucke C, Fischer G

Oligopeptide cyclophilin inhibitors: a reassessment.

Eur J Med Chem. 2011 Nov;46(11):5556-61. doi: 10.1016/j.ejmech.2011.09.019. Epub 2011 Sep 21.

PubMed ID
21963115 [ View in PubMed
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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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
CyclosporinePeptidyl-prolyl cis-trans isomerase AKd (nM)7.6N/AN/ADetails
CyclosporinePeptidyl-prolyl cis-trans isomerase AIC 50 (nM)9.3N/AN/ADetails