Thioxylated cyclosporin A for studying protein-drug interactions

Bioorg Med Chem Lett. 2016 Dec 1;26(23):5754-5756. doi: 10.1016/j.bmcl.2016.10.050. Epub 2016 Oct 17.

Abstract

Single atom substitution of cyclosporin A (CsA) through thioxylation has been used to study the structure-activity relationship of the immunosuppressive complex, involving the CsA receptor protein cyclophilin 18 (Cyp18) and the immunological target protein phosphatase calcineurin (CaN), illustrating the contributions of peptide backbone in protein-drug interaction. Moreover, the subtle difference between thioxylation positions in CsA has led to a remarkable change in the quenching effect on Cyp18 intrinsic fluorescence. Using the thioxylated compound Cs7 as an isosteric derivative of CsA in competition assay, the experiment has led to the determination of koff value in solution. Whereas the conformational heterogeneity of CsA has been found to be associated with its two-phase binding kinetics to Cyp18, the dissociation rate of CsA from complex is independent from the initial ligand structure.

Keywords: Calcineurin; Cyclophilin 18; Cyclosporin A; Dissociation rate; Protein–drug interaction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcineurin / metabolism
  • Cyclophilins / metabolism
  • Cyclosporine / chemistry*
  • Cyclosporine / pharmacology*
  • Humans
  • Immunosuppressive Agents / chemistry*
  • Immunosuppressive Agents / pharmacology*
  • Kinetics
  • Models, Molecular
  • Protein Binding

Substances

  • Immunosuppressive Agents
  • cyclophilin 19
  • Cyclosporine
  • Calcineurin
  • Cyclophilins