ArticleChemistry (Weinheim an der Bergstrasse, Germany)2022
Structural Insights into Pixatimod (PG545) Inhibition of Heparanase, a Key Enzyme in Cancer and Viral Infections.
Article in Chemistry (Weinheim an der Bergstrasse, Germany), 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 24 citations in OpenAlex.
- A one-step chemical derivatization strategy for mass spectrometric characterization of synthetic mimetics of sulfated glycosaminoglycans.Analytical methods : advancing methods and applications · 2026Article
- Investigation into the binding domains of platelet factor 4 unlocks new avenues for the design and synthesis of selective sulfated pseudo-tetrasaccharide aminoglycoside ligands.European journal of medicinal chemistry · 2025Article
- From Docking and Molecular Dynamics to Experimental Discovery: Exploring the Hydrophobic Landscapes of Heparanase to Design Potent Inhibitors.Journal of chemical information and modeling · 2025Article
- Could Hydrophobicity of Sulfated Pseudo-Trisaccharides Derived from Repurposing Aminoglycoside Tobramycin Modulate the Enzymatic Activity of Heparanase?Journal of medicinal chemistry · 2025Article
- Design of Paromomycin and Neomycin as Sulfated and Hydrophobic Glycans to Target Heparanase-Driven Tumor Progression and Metastasis.Journal of medicinal chemistry · 2025Article
- Extracellular matrix dysregulation in aging, calcification, and cancer diseases: insights into cellular senescence, inflammation, and novel therapeutic strategies.International journal of biological sciences · 2025Review
- Multifaceted Heparin: Diverse Applications beyond Anticoagulant Therapy.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Glycosaminoglycan microarrays for studying glycosaminoglycan-protein systems.Carbohydrate polymers · 2024Review
- Block Synthesis and Step-Growth Polymerization of C-6-Sulfonatomethyl-Containing Sulfated Malto-Oligosaccharides and Their Biological Profiling.International journal of molecular sciences · 2024Article
- Fucoidan's Molecular Targets: A Comprehensive Review of Its Unique and Multiple Targets Accounting for Promising Bioactivities Supported by In Silico Studies.Marine drugs · 2023Review
- Designing Smaller, Synthetic, Functional Mimetics of Sulfated Glycosaminoglycans as Allosteric Modulators of Coagulation Factors.Journal of medicinal chemistry · 2023Review
- Heparin, Heparan Sulphate and Sepsis: Potential New Options for Treatment.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Antiviral Disaccharide Lead Compounds against SARS-CoV-2 through Computer-Aided High-Throughput Screen.Chembiochem : a European journal of chemical biology · 2022Article
- Sulfated Hyaluronan Binds to Heparanase and Blocks Its Enzymatic and Cellular Actions in Carcinoma Cells.International journal of molecular sciences · 2022Article
- Structural Insights into Pixatimod (PG545) Inhibition of Heparanase, a Key Enzyme in Cancer and Viral Infections.Chemistry (Weinheim an der Bergstrasse, Germany) · 2022Article
Corrections and comments
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Authors and funding
6 authors at 5 institutions in 2 countries.
Funding
Abstract
Pixatimod (PG545), a heparan sulfate (HS) mimetic and anticancer agent currently in clinical trials, is a potent inhibitor of heparanase. Heparanase is an endo-β-glucuronidase that degrades HS in the extracellular matrix and basement membranes and is implicated in numerous pathological processes such as cancer and viral infections, including SARS-CoV-2. To understand how PG545 interacts with heparanase, we firstly carried out a conformational analysis through a combination of NMR experiments and molecular modelling which showed that the reducing end β-D-glucose residue of PG545 adopts a distorted conformation. This was followed by docking and molecular dynamics simulations to study the interactions of PG545 with heparanase, revealing that PG545 is able to block the active site by binding in different conformations, with the cholestanol side-chain making important hydrophobic interactions. While PG545 blocks its natural substrate HS from binding to the active site, small synthetic heparanase substrates are only partially excluded, and thus pentasaccharide or larger substrates are preferred for assaying this class of inhibitor. This study provides new insights for the design of next-generation heparanase inhibitors and substrates.
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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.