7YI7

Crystal structure of Human HPSE1 in complex with inhibitor

Summary for 7YI7

• Entry DOI: 10.2210/pdb7yi7/pdb
• Descriptor: Heparanase 50 kDa subunit, Heparanase 8 kDa subunit, (5~{S},6~{R},7~{S},8~{S})-6,7,8-tris(oxidanyl)-2-[2-[4-(trifluoromethyl)phenyl]ethyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-5-carboxylic acid, ... (4 entities in total)
• Functional Keywords: endo-glucoronidase, heparanase-1, hep, hpa, hpa1, hpr1, hpse1, hse1, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 52123.91

Authors

Mima, M.,Fujimoto, N.,Imai, Y. (deposition date: 2022-07-15, release date: 2022-12-07, Last modification date: 2024-10-23)

Primary citation

Imai, Y.,Wakasugi, D.,Suzuki, R.,Kato, S.,Sugisaki, M.,Mima, M.,Miyagawa, H.,Endo, M.,Fujimoto, N.,Fukunaga, T.,Kato, S.,Kuroda, S.,Takahashi, T.,Kakinuma, H.
Lead identification of novel tetrahydroimidazo[1,2-a]pyridine-5-carboxylic acid derivative as a potent heparanase-1 inhibitor.
Bioorg.Med.Chem.Lett., 79:129050-129050, 2022

PubMed Abstract: Heparanase-1 (HPSE1) is an endo-β-d-glucuronidase that cleaves heparan sulfate proteoglycans into short-chain heparan sulfates (HS). The inhibition of HPSE1 has therapeutic potential for proteinuric diseases such as nephrotic syndrome because increased HPSE1 expression is associated with the loss of HS in the glomerular basement membrane, leading to the development of proteinuria. The present study examined the generation of a lead compound focusing on chemical structures with a sugar moiety, such as glycosides and sugar analogs, taking their physical properties into consideration. Compound 10, an exo-β-d-glucuronidase (GUSβ) inhibitor, was found to have a weak inhibitory activity against endo-β-d-glucuronidase HPSE1. A structure-activity relationship study using the X-ray co-crystal structure of 10 and HPSE1 resulted in 12a, which showed a more than 14-fold increase in HPSE1 inhibitory activity compared with that of 10. Compound 12a could be a novel lead compound for the development of a potent HPSE1 inhibitor.

PubMed: 36368497
DOI: 10.1016/j.bmcl.2022.129050

Experimental method

X-RAY DIFFRACTION (2.8 Å)