ArticleGlycobiology2016
Kinetic analysis and molecular modeling of the inhibition mechanism of roneparstat (SST0001) on human heparanase.
Article in Glycobiology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 68 citations in OpenAlex.
- Non-anticoagulant heparins: glycan-mediated immune modulation and therapeutic applications.Frontiers in immunology · 2026Review
- A Novel Drug Candidate for Sepsis Targeting Heparanase by Inhibiting Cytokine Storm.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Design Principle of Heparanase Inhibitors: A Combined In Vitro and In Silico Study.ACS medicinal chemistry letters · 2024Article
- Insights into potential mechanisms of asthma patients with COVID-19: A study based on the gene expression profiling of bronchoalveolar lavage fluid.Computers in biology and medicine · 2022Article
- Sulfated Hyaluronan Binds to Heparanase and Blocks Its Enzymatic and Cellular Actions in Carcinoma Cells.International journal of molecular sciences · 2022Article
- Heparanase Blockade as a Novel Dual-Targeting Therapy for COVID-19.Journal of virology · 2022Article
- Structural Insights into Pixatimod (PG545) Inhibition of Heparanase, a Key Enzyme in Cancer and Viral Infections.Chemistry (Weinheim an der Bergstrasse, Germany) · 2022Article
- Heparin prevents in vitro glycocalyx shedding induced by plasma from COVID-19 patients.Life sciences · 2021Article
- Heparan Sulfate Proteoglycans in Viral Infection and Treatment: A Special Focus on SARS-CoV-2.International journal of molecular sciences · 2021Review
- Computational Investigation Identified Potential Chemical Scaffolds for Heparanase as Anticancer Therapeutics.International journal of molecular sciences · 2021Article
- Glycosaminoglycans: Carriers and Targets for Tailored Anti-Cancer Therapy.Biomolecules · 2021Review
- Heparan Sulfate Glycosaminoglycans: (Un)Expected Allies in Cancer Clinical Management.Biomolecules · 2021Review
- Review
- Heparanase-enhanced Shedding of Syndecan-1 and Its Role in Driving Disease Pathogenesis and Progression.The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society · 2020Review
- Beneficial non-anticoagulant mechanisms underlying heparin treatment of COVID-19 patients.EBioMedicine · 2020Review
- Heparanase promotes myeloma stemness and in vivo tumorigenesis.Matrix biology : journal of the International Society for Matrix Biology · 2020Article
- Identification and Repurposing of Trisubstituted Harmine Derivatives as Novel Inhibitors ofMolecules (Basel, Switzerland) · 2020Article
- Non-Anticoagulant Heparins as Heparanase Inhibitors.Advances in experimental medicine and biology · 2020Review
- Heparanase: A Dynamic Promoter of Myeloma Progression.Advances in experimental medicine and biology · 2020Review
- Heparin Binding Proteins as Therapeutic Target: An Historical Account and Current Trends.Medicines (Basel, Switzerland) · 2019Review
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Heparanase is a β-d-glucuronidase which cleaves heparan sulfate chains in the extracellular matrix and on cellular membranes. A dysregulated heparanase activity is intimately associated with cell invasion, tumor metastasis and angiogenesis, making heparanase an attractive target for the development of anticancer therapies. SST0001 (roneparstat; Sigma-Tau Research Switzerland S.A.) is a non-anticoagulant 100% N-acetylated and glycol-split heparin acting as a potent heparanase inhibitor, currently in phase I in advanced multiple myeloma. Herein, the kinetics of heparanase inhibition by roneparstat is reported. The analysis of dose-inhibition curves confirmed the high potency of roneparstat (IC50 ≈ 3 nM) and showed, at higher concentrations, a Hill coefficient consistent with the engagement of two molecules of inhibitor. A homology model of human heparanase GS3 construct was built and used for docking experiments with inhibitor fragments. The model has high structural similarity with the recently reported crystal structure of human heparanase. Different interaction schemes are proposed, which support the hypothesis of a complex binding mechanism involving the recruitment of one or multiple roneparstat chains, depending on its concentration. In particular, docking solutions were obtained in which (i) a single roneparstat molecule interacts with both heparin-binding domains (HBDs) of heparanase or (ii) two fragments of roneparstat interact with either HBD-1 or HBD-2, consistent with the possibility of different inhibitor:enzyme binding stoichiometries. This study provides unique insights into the mode of action of roneparstat as well as clues of its interaction with heparanase at a molecular level, which could be exploited to design novel potential inhibitor molecules.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.