Complex Inhibitory Mechanism of Glycomimetics with Heparanase.
Biochemistry
; 62(14): 2202-2215, 2023 07 18.
Article
in En
| MEDLINE
| ID: mdl-37368361
ABSTRACT
Heparanase (HPSE) is the only mammalian endo-ß-glucuronidase known to catalyze the degradation of heparan sulfate. Dysfunction of HPSE activity has been linked to several disease states, resulting in HPSE becoming the target of numerous therapeutic programs, yet no drug has passed clinical trials to date. Pentosan polysulfate sodium (PPS) is a heterogeneous, FDA-approved drug for the treatment of interstitial cystitis and a known HPSE inhibitor. However, due to its heterogeneity, characterization of its mechanism of HPSE inhibition is challenging. Here, we show that inhibition of HPSE by PPS is complex, involving multiple overlapping binding events, each influenced by factors such as oligosaccharide length and inhibitor-induced changes in the protein secondary structure. The present work advances our molecular understanding of the inhibition of HPSE and will aid in the development of therapeutics for the treatment of a broad range of pathologies associated with enzyme dysfunction, including cancer, inflammatory disease, and viral infections.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Glucuronidase
/
Heparitin Sulfate
Limits:
Animals
Language:
En
Journal:
Biochemistry
Year:
2023
Document type:
Article