Interpreting the behavior of concentration-response curves of hyaluronidase inhibitors under DMSO-perturbed assay conditions

Bioorg Med Chem Lett. 2016 Jul 1;26(13):3153-3157. doi: 10.1016/j.bmcl.2016.04.082. Epub 2016 Apr 28.

Abstract

Hyaluronan-degrading enzyme (hyaluronidase) is involved in tumor growth and inflammation, and as such, hyaluronidase inhibitors have received recent attention as potential therapeutics. The previous studies have successfully discovered a wide range of inhibitors, but unfortunately most of them are dissimilar to original ligand hyaluronan and the mode of action is poorly understood. The present study mechanistically characterized these structurally unrelated inhibitors by interpreting the behavior of concentration-response curves under several in vitro assay conditions. Detergent-addition conditions definitely identified aggregation-based inhibitors. Subsequently, DMSO-perturbed conditions, though preliminary, highlighted the inhibitors that might bind to enzyme non-specifically. Here, an intriguing implication of the latter description is that DMSO-perturbed conditions would generate non-productive but not-denatured enzyme that is an assembly of effective species to capture non-specific binding molecules, and thereby would attenuate their inhibitory activities.

Keywords: Concentration–response curve; DMSO; Hyaluronidase inhibitor; Non-specific binding; Perturbation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chondroitin Sulfates / chemical synthesis
  • Chondroitin Sulfates / chemistry
  • Chondroitin Sulfates / pharmacology
  • Cromolyn Sodium / chemical synthesis
  • Cromolyn Sodium / chemistry
  • Cromolyn Sodium / pharmacology
  • Dimethyl Sulfoxide / chemistry*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Flavonoids / chemical synthesis
  • Flavonoids / chemistry
  • Flavonoids / pharmacology
  • Glycyrrhizic Acid / chemical synthesis
  • Glycyrrhizic Acid / chemistry
  • Glycyrrhizic Acid / pharmacology
  • Hyaluronoglucosaminidase / antagonists & inhibitors*
  • Hyaluronoglucosaminidase / metabolism
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Flavonoids
  • baicalin
  • Glycyrrhizic Acid
  • Chondroitin Sulfates
  • Hyaluronoglucosaminidase
  • Cromolyn Sodium
  • Dimethyl Sulfoxide