Improved Surface Display of Human Hyal1 and Identification of Testosterone Propionate and Chicoric Acid as New Inhibitors

Autor: Marc Le Borgne, Joachim Jose, Isabelle Lengers, Fabian C. Herrmann
Přispěvatelé: Westfälische Wilhelms-Universität Münster (WWU), Molécules bioactives et chimie médicinale (B2MC), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
Testosterone propionate
medicine.medical_treatment
Pharmaceutical Science
lcsh:Medicine
lcsh:RS1-441
hyaluronidase
[CHIM.THER]Chemical Sciences/Medicinal Chemistry
medicine.disease_cause
Article
Steroid
lcsh:Pharmacy and materia medica
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
[SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication
Hyaluronidase
Drug Discovery
hyaluronic acid
inhibitors
medicine
Escherichia coli
IC50
chemistry.chemical_classification
biology
Chemistry
Drug discovery
lcsh:R
hyal1
Enzyme assay
3. Good health
030104 developmental biology
Enzyme
autodisplay
Biochemistry
030220 oncology & carcinogenesis
biology.protein
[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology
Molecular Medicine
medicine.drug
Zdroj: Pharmaceuticals
Pharmaceuticals, Vol 13, Iss 4, p 54 (2020)
Volume 13
Issue 4
Pharmaceuticals, MDPI, 2020, 13 (4), pp.54. ⟨10.3390/ph13040054⟩
ISSN: 1424-8247
Popis: Degradation of high molecular weight hyaluronic acid (HA) in humans is mainly catalyzed by hyaluronidase Hyal1. This enzyme is involved in many pathophysiological processes and therefore appears an interesting target for drug discovery. Until now, only a few inhibitors of human Hyal1 are known due to obstacles in obtaining active enzymes for inhibitor screening. The aim of the present work was to provide a convenient enzyme activity assay and show its feasibility by the identification of new inhibitors. By autodisplay, Escherichia coli F470 can present active Hyal1 on its surface. In this study, the inducible expression of Hyal1 on the cell surface of E. coli under the control of a rhamnose-dependent promoter (Prha) was performed and optimized. Enzyme activity per single cell was increased by a factor of 100 compared to the constitutive Hyal1 surface display, as described before. An activity of 6.8 ×
10-4 mU per single cell was obtained under optimal reaction conditions. By this modified activity assay, two new inhibitors of human Hyal1 were identified. Chicoric acid, a natural compound belonging to the phenylpropanoids, showed an IC50 value of 171 µ
M. The steroid derivative testosterone propionate showed and IC50 value of 124 ±
1.1 µ
M. Both values were in the same order of magnitude as the IC50 value of glycyrrhizic acid (177 µ
M), one of the best known inhibitors of human Hyal1 known so far. In conclusion, we established a new enzyme activity assay for human Hyal1 and identified new inhibitors with this new assay method.
Databáze: OpenAIRE
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