Dynamic Covalent Identification of an Efficient Heparin Ligand

Corredor, Miriam; Carbajo, Daniel; Domingo, Cecilia; Pérez, Yolanda; Bujons, Jordi; Messeguer, Ángel; Alfonso, Ignacio

doi:10.1002/ange.201806770

Cited by 9 publications

(2 citation statements)

References 47 publications

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“…Others, such as GAGs mimetics, cationic macromolecules (proteins, polymers, dendrimers), or small molecules, could be more selective. Some investigations have reported small molecules as antagonists of heparin or heparan sulfate [ 69 , 70 ]. To effectively design small molecule inhibitor of protein–GAG interactions, structural details about the specific location of the binding/interaction site is highly desirable.…”

Section: Discussionmentioning

confidence: 99%

Semaphorin 3A—Glycosaminoglycans Interaction as Therapeutic Target for Axonal Regeneration

et al. 2021

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Semaphorin 3A (Sema3A) is a cell-secreted protein that participates in the axonal guidance pathways. Sema3A acts as a canonical repulsive axon guidance molecule, inhibiting CNS regenerative axonal growth and propagation. Therefore, interfering with Sema3A signaling is proposed as a therapeutic target for achieving functional recovery after CNS injuries. It has been shown that Sema3A adheres to the proteoglycan component of the extracellular matrix (ECM) and selectively binds to heparin and chondroitin sulfate-E (CS-E) glycosaminoglycans (GAGs). We hypothesize that the biologically relevant interaction between Sema3A and GAGs takes place at Sema3A C-terminal polybasic region (SCT). The aims of this study were to characterize the interaction of the whole Sema3A C-terminal polybasic region (Sema3A 725–771) with GAGs and to investigate the disruption of this interaction by small molecules. Recombinant Sema3A basic domain was produced and we used a combination of biophysical techniques (NMR, SPR, and heparin affinity chromatography) to gain insight into the interaction of the Sema3A C-terminal domain with GAGs. The results demonstrate that SCT is an intrinsically disordered region, which confirms that SCT binds to GAGs and helps to identify the specific residues involved in the interaction. NMR studies, supported by molecular dynamics simulations, show that a new peptoid molecule (CSIC02) may disrupt the interaction between SCT and heparin. Our structural study paves the way toward the design of new molecules targeting these protein–GAG interactions with potential therapeutic applications.

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Section: Discussionmentioning

confidence: 99%

Semaphorin 3A—Glycosaminoglycans Interaction as Therapeutic Target for Axonal Regeneration

et al. 2021

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“…It was designed specifically to interact with heparin on the basis of charge, and, it seems by chance, has also been found to bind to direct oral anticoagulants (DOACs) and neutralize their activity (Ansell et al, 2021). At a much earlier stage of development for medicinal application, the use of a dynamic covalent selection approach has led to the identification and synthesis of a dialkylated spermine with low micromolar affinity for heparin, capable of neutralizing anti-Xa activity in a chromogenic assay (Corredor et al, 2018).…”

Section: B Neutralization Of Heparin By Protamine and Other Compoundsmentioning

confidence: 99%

Pharmacology of Heparin and Related Drugs: An Update

et al. 2023

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Live‐Cell‐Templated Dynamic Combinatorial Chemistry

et al. 2020

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Dynamic covalent chemistry combines in a single step the screening and synthesis of ligands for biomolecular recognition. In order to do that, a chemical entity is used as template within a dynamic combinatorial library of interconverting species, so that the stronger binders are amplified due to the efficient interaction with the target. Here we employed whole A549 living cells as template in a dynamic mixture of imines, for which amplification reflects the efficient and selective interaction with the corresponding extracellular matrix. The amplified polyamine showed strong interaction with the A549 extracellular matrix in on‐cell NMR experiments, while combination of NMR, SPR, and molecular dynamics simulations in model systems provided insights on the molecular recognition event. Notably, our work pioneers the use of whole living cells in dynamic combinatorial chemistry, which paves the way towards the discovery of new bioactive molecules in a more biorelevant environment.

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Dynamic Covalent Identification of an Efficient Heparin Ligand

Abstract: Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.

Cited by 9 publications

References 47 publications

Semaphorin 3A—Glycosaminoglycans Interaction as Therapeutic Target for Axonal Regeneration

Semaphorin 3A—Glycosaminoglycans Interaction as Therapeutic Target for Axonal Regeneration

Pharmacology of Heparin and Related Drugs: An Update

Live‐Cell‐Templated Dynamic Combinatorial Chemistry

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