Preclinical characterization of naturally occurring polyketide cyclophilin inhibitors from the sanglifehrin family

Antimicrob Agents Chemother. 2011 May;55(5):1975-81. doi: 10.1128/AAC.01627-10. Epub 2011 Mar 7.


Cyclophilin inhibitors currently in clinical trials for hepatitis C virus (HCV) are all analogues of cyclosporine (CsA). Sanglifehrins are a group of naturally occurring cyclophilin binding polyketides that are structurally distinct from the cyclosporines and are produced by a microorganism amenable to biosynthetic engineering for lead optimization and large-scale production by fermentation. Preclinical characterization of the potential utility of this class of compounds for the treatment of HCV revealed that the natural sanglifehrins A to D are all more potent than CsA at disrupting formation of the NS5A-CypA, -CypB, and -CypD complexes and at inhibition of CypA, CypB, and CypD isomerase activity. In particular, sanglifehrin B (SfB) was 30- to 50-fold more potent at inhibiting the isomerase activity of all Cyps tested than CsA and was also shown to be a more potent inhibitor of the 1b subgenomic replicon (50% effective concentrations [EC50s] of 0.070 μM and 0.16 μM in Huh 5-2 and Huh 9-13 cells, respectively). Physicochemical and mouse pharmacokinetic analyses revealed low oral bioavailability (F<4%) and low solubility (<25 μM), although the half-lives (t1/2) of SfA and SfB in mouse blood after intravenous (i.v.) dosing were long (t1/2>5 h). These data demonstrate that naturally occurring sanglifehrins are suitable lead compounds for the development of novel analogues that are less immunosuppressive and that have improved metabolism and pharmacokinetic properties.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Blotting, Western
  • Cell Line
  • Cyclophilins / antagonists & inhibitors*
  • Enzyme-Linked Immunosorbent Assay
  • Hep G2 Cells
  • Hepacivirus / drug effects
  • Humans
  • Lactones / chemistry
  • Lactones / pharmacology*
  • Male
  • Mice
  • Molecular Structure
  • Virus Replication / drug effects


  • Antiviral Agents
  • Lactones
  • Cyclophilins