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1. Identification of disease treatment mechanisms through the multiscale interactome

   https://doi.org/10.1038/s41467-021-21770-8  

   Ruiz, Camilo; Zitnik, Marinka; Leskovec, Jure (December 2021, Nature Communications)

   null (Ed.)

   Abstract Most diseases disrupt multiple proteins, and drugs treat such diseases by restoring the functions of the disrupted proteins. How drugs restore these functions, however, is often unknown as a drug’s therapeutic effects are not limited to the proteins that the drug directly targets. Here, we develop the multiscale interactome, a powerful approach to explain disease treatment. We integrate disease-perturbed proteins, drug targets, and biological functions into a multiscale interactome network. We then develop a random walk-based method that captures how drug effects propagate through a hierarchy of biological functions and physical protein-protein interactions. On three key pharmacological tasks, the multiscale interactome predicts drug-disease treatment, identifies proteins and biological functions related to treatment, and predicts genes that alter a treatment’s efficacy and adverse reactions. Our results indicate that physical interactions between proteins alone cannot explain treatment since many drugs treat diseases by affecting the biological functions disrupted by the disease rather than directly targeting disease proteins or their regulators. We provide a general framework for explaining treatment, even when drugs seem unrelated to the diseases they are recommended for. 

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2. Heparan sulfate glycomimetics via iterative assembly of “clickable” disaccharides

   https://doi.org/10.1039/D3SC00260H  

   Yang, Cangjie; Deng, Yu; Wang, Yang; Xia, Chaoshuang; Mehta, Akul Y.; Baker, Kelly J.; Samal, Anuj; Booneimsri, Putthipong; Lertmaneedang, Chanthakarn; Hwang, Seung; et al (March 2023, Chemical Science)

   Heparan sulfate (HS) glycosaminoglycans are widely expressed on the mammalian cell surfaces and extracellular matrices and play important roles in a variety of cell functions. Studies on the structure–activity relationships of HS have long been hampered by the challenges in obtaining chemically defined HS structures with unique sulfation patterns. Here, we report a new approach to HS glycomimetics based on iterative assembly of clickable disaccharide building blocks that mimic the disaccharide repeating units of native HS. Variably sulfated clickable disaccharides were facilely assembled into a library of mass spec-sequenceable HS-mimetic oligomers with defined sulfation patterns by solution-phase iterative syntheses. Microarray and surface plasmon resonance (SPR) binding assays corroborated molecular dynamics (MD) simulations and confirmed that these HS-mimetic oligomers bind protein fibroblast growth factor 2 (FGF2) in a sulfation-dependent manner consistent with that of the native HS. This work established a general approach to HS glycomimetics that can potentially serve as alternatives to native HS in both fundamental research and disease models. 

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3. SPR Sensor-Based Analysis of the Inhibition of Marine Sulfated Glycans on Interactions between Monkeypox Virus Proteins and Glycosaminoglycans

   https://doi.org/10.3390/md21050264  

   He, Peng; Shi, Deling; Li, Yunran; Xia, Ke; Kim, Seon Beom; Dwivedi, Rohini; Farrag, Marwa; Pomin, Vitor H.; Linhardt, Robert J.; Dordick, Jonathan S.; et al (May 2023, Marine Drugs)

   Sulfated glycans from marine organisms are excellent sources of naturally occurring glycosaminoglycan (GAG) mimetics that demonstrate therapeutic activities, such as antiviral/microbial infection, anticoagulant, anticancer, and anti-inflammation activities. Many viruses use the heparan sulfate (HS) GAG on the surface of host cells as co-receptors for attachment and initiating cell entry. Therefore, virion–HS interactions have been targeted to develop broad-spectrum antiviral therapeutics. Here we report the potential anti-monkeypox virus (MPXV) activities of eight defined marine sulfated glycans, three fucosylated chondroitin sulfates, and three sulfated fucans extracted from the sea cucumber species Isostichopus badionotus, Holothuria floridana, and Pentacta pygmaea, and the sea urchin Lytechinus variegatus, as well as two chemically desulfated derivatives. The inhibitions of these marine sulfated glycans on MPXV A29 and A35 protein–heparin interactions were evaluated using surface plasmon resonance (SPR). These results demonstrated that the viral surface proteins of MPXV A29 and A35 bound to heparin, which is a highly sulfated HS, and sulfated glycans from sea cucumbers showed strong inhibition of MPXV A29 and A35 interactions. The study of molecular interactions between viral proteins and host cell GAGs is important in developing therapeutics for the prevention and treatment of MPXV. 

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4. Interactions between heparin and SARS-CoV-2 spike glycoprotein RBD from omicron and other variants

   https://doi.org/10.3389/fmolb.2022.912887  

   Gelbach, Adrianne L.; Zhang, Fuming; Kwon, Seok-Joon; Bates, John T.; Farmer, Andrew P.; Dordick, Jonathan S.; Wang, Chunyu; Linhardt, Robert J. (August 2022, Frontiers in Molecular Biosciences)

   Heparan sulfate (HS) acts as a co-receptor of angiotensin-converting enzyme 2 (ACE2) by interacting with severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) spike glycoprotein (SGP) facilitating host cell entry of SARS-CoV-2 virus. Heparin, a highly sulfated version of heparan sulfate (HS), interacts with a variety of proteins playing key roles in many physiological and pathological processes. In this study, SARS-CoV-2 SGP receptor binding domain (RBD) wild type (WT), Delta and Omicron variants were expressed in Expi293F cells and used in the kinetic and structural analysis on their interactions with heparin. Surface plasmon resonance (SPR) analysis showed the binding kinetics of SGP RBD from WT and Delta variants were very similar while Omicron variant SGP showed a much higher association rate. The SGP from Delta and Omicron showed higher affinity ( K D ) to heparin than the WT SGP. Competition SPR studies using heparin oligosaccharides indicated that binding of SGP RBDs to heparin requires chain length greater than 18. Chemically modified heparin derivatives all showed reduced interactions in competition assays suggesting that all the sulfo groups in the heparin polysaccharide were critical for binding SGP RBDs with heparin. These interactions with heparin are pH sensitive. Acidic pH (pH 6.5, 5.5, 4.5) greatly increased the binding of WT and Delta SGP RBDs to heparin, while acidic pH slightly reduced the binding of Omicron SGP RBD to heparin compared to binding at pH 7.3. In contrast, basic pH (pH 8.5) greatly reduced the binding of Omicron SGP RBDs to heparin, with much less effects on WT or Delta. The pH dependence indicates different charged residues were present at the Omicron SGP-heparin interface. Detailed kinetic and structural analysis of the interactions of SARS-CoV-2 SGP RBDs with heparin provides important information for designing anti-SARS-CoV-2 molecules. 

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5. Probing Glycosaminoglycan–Protein Interactions: Applications of Surface Plasmon Resonance

   https://doi.org/10.3390/bios16020071  

   Bu, Changkai; Pan, Lin; Chi, Lianli; Pomin, Vitor H; Dordick, Jonathan S; Wang, Chunyu; Zhang, Fuming (February 2026, Biosensors)

   Glycosaminoglycans (GAGs) are highly negatively charged polysaccharides that play essential roles in numerous physiological and pathological processes through their interactions with proteins. These interactions govern cellular signaling, inflammation, coagulation, and recognition. Surface Plasmon Resonance (SPR) has emerged as a key biophysical technique for label-free, real-time characterization of biomolecular interactions, offering insights into binding kinetics, affinity, and specificity. SPR-based approaches to glycosaminoglycan–protein interaction studies offer powerful tools for elucidating the roles of GAGs in a wide range of physiological and pathological processes. In this review, we systematically discuss experimental strategies, data analysis methods, and representative applications of SPR-based glycosaminoglycan–protein interactions. Special attention is given to the challenges associated with GAG heterogeneity and immobilization, as well as recent technological advances that enhance sensitivity and throughput. To our knowledge, this review represents one of the first systematic and up-to-date summaries specifically focused on recent advances in applying SPR to the study of glycosaminoglycan–protein interactions. 

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