title: Interpreting the behavior of concentration-response curves of hyaluronidase inhibitors under DMSO-perturbed assay conditions.
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.
authors.affiliation: Department of Hospital Pharmacy, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. Electronic address: tomohara@med.u-toyama.ac.jp.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Tomohara
authors.affiliation: Department of Hospital Pharmacy, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Ito
authors.affiliation: Department of Hospital Pharmacy, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
authors.forename: Saika
authors.initials: S
authors.lastname: Onikata
authors.affiliation: Department of Hospital Pharmacy, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
authors.forename: Kota
authors.initials: K
authors.lastname: Furusawa
authors.affiliation: Department of Hospital Pharmacy, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kato
authors.affiliation: Department of Hospital Pharmacy, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. Electronic address: adachi@med.u-toyama.ac.jp.
authors.forename: Isao
authors.initials: I
authors.lastname: Adachi
mesh_terms: D002809:Chondroitin Sulfates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004205:Cromolyn Sodium / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004121:Dimethyl Sulfoxide / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005419:Flavonoids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019695:Glycyrrhizic Acid / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006821:Hyaluronoglucosaminidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D005419:Flavonoids; C038044:baicalin; D019695:Glycyrrhizic Acid; D002809:Chondroitin Sulfates; D006821:Hyaluronoglucosaminidase; D004205:Cromolyn Sodium; D004121:Dimethyl Sulfoxide
keywords: Concentration–response curve; DMSO; Hyaluronidase inhibitor; Non-specific binding; Perturbation