Roland Pieters | Universiteit Utrecht (original) (raw)

Papers by Roland Pieters

Molecules, Apr 17, 2018

A series of sp 2-iminosugar glycomimetics differing in the reducing or nonreducing character, the... more A series of sp 2-iminosugar glycomimetics differing in the reducing or nonreducing character, the configurational pattern (D-gluco or Lido), the architecture of the glycone skeleton, and the nature of the nonglycone substituent has been synthesized and assayed for their inhibition properties towards commercial glycosidases. On the basis of their affinity and selectivity towards GH1 β-glucosidases, reducing and nonreducing bicyclic derivatives having a hydroxylation profile of structural complementarity with D-glucose and incorporating an N-octyl-isourea or-isothiourea segment were selected for further evaluation of their inhibitory/chaperoning potential against human glucocerebrosidase (GCase). The 1-deoxynojirimycin (DNJ)-related nonreducing conjugates behaved as stronger GCase inhibitors than the reducing counterparts and exhibited potent chaperoning capabilities in Gaucher fibroblasts hosting the neuronopathic G188S/G183W mutation, the isothiourea derivative being indeed one of the most efficient chaperone candidates reported up to date (70% activity enhancement at 20 pM). At their optimal concentration, the four selected compounds promoted mutant GCase activity enhancements over 3-fold; yet, the inhibitor/chaperoning balance became unfavorable at much lower concentration for nonreducing as compared to reducing derivatives.

Arkivoc, Mar 21, 2021

Multivalent interactions exist everywhere in nature. Here we will summarize the available data of... more Multivalent interactions exist everywhere in nature. Here we will summarize the available data of multivalency effects that were explored for the design of novel neuraminidase (NA) inhibitors of influenza virus A. Although multivalency is a most effective tool to achieve high binding affinity, the molecular mechanisms are still poorly understood. The potency of multivalent neuraminidase inhibitors (NAIs) are dependent on the length, rigidity and chemical composition of the linker, ligand chemical structure and also the density of the ligand display. Important issues such as potential side-effects, drug-resistance, bioavailability and pharmacokinetics are largely unexplored with respect to application. The multivalent NAIs reported so far were of surprising potency and may play a role in therapeutic application and may prove valuable in forecasted pandemics .

Biomolecules, Nov 18, 2021

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

ChemistryOpen, Mar 9, 2015

Journal of Medicinal Chemistry, Nov 11, 2004

Fungal and bacterial pathogens causing lung infections often use lectins to mediate adhesion to g... more Fungal and bacterial pathogens causing lung infections often use lectins to mediate adhesion to glycoconjugates at the surface of host tissues. Given the rapid emergence of resistance to the treatments in current use, β-propeller lectins such as FleA from Aspergillus fumigatus, SapL1 from Scedosporium apiospermum, and BambL from Burkholderia ambifaria have become appealing targets for the design of anti-adhesive molecules. In search of novel and cheap anti-infectious agents, we synthesized multivalent compounds that can display up to 20 units of fucose, the natural ligand. We obtained nanomolar inhibitors that are several orders of magnitude stronger than their monovalent analogue according to several biophysical techniques (i.e., fluorescence polarization, isothermal titration calorimetry, and bio-layer interferometry). The reason for high affinity might be attributed to a strong aggregating mechanism, which was examined by analytical ultracentrifugation. Additional techniques in s...

Arkivoc, 2021

Biomolecules, 2021

Galectin-7 is a soluble unglycosylated lectin that is able to bind specifically to β-galactosides... more Galectin-7 is a soluble unglycosylated lectin that is able to bind specifically to β-galactosides. It has been described to be involved in apoptosis, proliferation and differentiation, but also in cell adhesion and migration. Several disorders and diseases are discussed by covering the aforementioned biological processes. Structural features of galectin-7 are discussed as well as targeting the protein intracellularly or extracellularly. The exact molecular mechanisms that lie behind many biological processes involving galectin-7 are not known. It is therefore useful to come up with chemical probes or tools in order to obtain knowledge of the physiological processes. The objective of this review is to summarize the roles and functions of galectin-7 in the human body, providing reasons why it is necessary to design inhibitors for galectin-7, to give the reader structural insights and describe its current inhibitors.

Journal of Medicinal Chemistry, 2021

Shiga toxin is an AB 5 toxin produced by Shigella species, while related toxins are produced by S... more Shiga toxin is an AB 5 toxin produced by Shigella species, while related toxins are produced by Shiga toxin-producing Escherichia coli (STEC). Infection by Shigella can lead to bloody diarrhea followed by the often fatal hemolytic uremic syndrome (HUS). In the present paper, we aimed for a simple and effective toxin inhibitor by comparing three classes of carbohydrate-based inhibitors: glycodendrimers, glycopolymers, and oligosaccharides. We observed a clear enhancement in potency for multivalent inhibitors, with the divalent and tetravalent compounds inhibiting in the millimolar and micromolar range, respectively. However, the polymeric inhibitor based on galabiose was the most potent in the series exhibiting nanomolar inhibition. Alginate and chitosan oligosaccharides also inhibit Shiga toxin and may be used as a prophylactic drug during shigella outbreaks.

Organic & Biomolecular Chemistry, 2019

New hybrid glycopolymers were synthesized that contain two epitopes blocking GM1- and fucose-base... more New hybrid glycopolymers were synthesized that contain two epitopes blocking GM1- and fucose-based intoxication modes of the cholera toxin.

Faraday Discussions, 2019

Thermoresponsive receptors for the recognition unit of the cholera toxin (CTB) can recognise the ... more Thermoresponsive receptors for the recognition unit of the cholera toxin (CTB) can recognise the protein with nanomolar affinity. An increase in temperature can drastically reduce their avidity, enabling on-demand release of CTB.

Journal of Medicinal Chemistry, 2019

Multivalent carbohydrate-based ligands were synthesized and evaluated as inhibitors of the adhesi... more Multivalent carbohydrate-based ligands were synthesized and evaluated as inhibitors of the adhesion protein HA of the influenza A virus (IAV). HA relies on multivalency for strong viral adhesion. While viral adhesion inhibition by large polymeric molecules has proven viable, limited success was reached for smaller multivalent compounds. By linking of sialylated LAcNAc units to di-and trivalent scaffolds, inhibitors were obtained with an up to 428-fold enhanced inhibition in various assays.

The Journal of Organic Chemistry, 2019

Divalent ligands were prepared as inhibitors for the adhesion protein of the problematic Pseudomo... more Divalent ligands were prepared as inhibitors for the adhesion protein of the problematic Pseudomonas aeruginosa pathogen. Bridging two binding sites enables simultaneous binding of two galactose moieties, which strongly enhances binding. An alternating motif of glucose and triazole and aryl groups was shown to have the right mix of rigidity, solubility, and ease of synthesis. Spacers were varied with respect to the core unit as well as the aglycon portions in an attempt to optimize dynamics and enhance interactions with the protein. Affinities of the divalent ligands were measured by ITC, and K d 's as low as 12 nM were determined, notably for a compounds with either a rigid (phenyl) or flexible (butyl) unit at the core. Introducing a phenyl aglycon moiety next to the galactoside ligands on both termini did indeed lead to a higher enthalpy of binding, which was more than compensated by entropic costs. The results are discussed in terms of thermodynamics and theoretical calculations of the expected and observed multivalency effects.

Bioconjugate Chemistry, 2019

Cholera is a potentially fatal bacterial infection that affects a large number of people in devel... more Cholera is a potentially fatal bacterial infection that affects a large number of people in developing countries. It is caused by the cholera toxin (CT), an AB 5 toxin secreted by Vibrio cholera. The toxin comprises a toxic A-subunit and a pentameric B-subunit that bind to the intestinal cell surface. Several monovalent and multivalent inhibitors of the toxin have been synthesized but are too complicated and expensive for practical use in developing countries. Meta-nitrophenyl αgalactoside (MNPG) is a known promising ligand for CT, and here mono-and multivalent compounds based on MNPG were synthesized. We present the synthesis of MNPG in greatly improved yields and its use while linked to a multivalent scaffold. We used economical polymers as multivalent scaffolds, namely, polyacrylamide, dextran, and hyperbranched polyglycerols (hPGs). Copper-catalyzed alkyne azide cycloaddition reaction (CuAAC) produced the inhibitors that were tested in an ELISA-type assay and an intestinal organoid swelling inhibition assay. The inhibitory properties varied widely depending on the type of polymer, and the most potent conjugates showed IC 50 values in the nanomolar range.

Bioconjugate chemistry, Jan 18, 2018

Galectin inhibitors are urgently needed to understand the mode of action and druggability of diff... more Galectin inhibitors are urgently needed to understand the mode of action and druggability of different galectins, but potent and selective agents still evade researchers. Small-sized inhibitors based on thiodigalactoside (TDG) have shown their potential while modifications at their C3 position indicated a strategy to improve selectivity and potency. Considering the role of galectins as glycoprotein traffic police, involved in multivalent bridging interactions, we aimed to create multivalent versions of the potent TDG inhibitors. We herein present for the first time the multivalent attachment of a TDG derivative using bovine serum albumin (BSA) as the scaffold. An efficient synthetic method is presented to obtain a novel type of neoglycosylated proteins loaded with different numbers of TDG moieties. A polyethylene glycol (PEG)-spacer is introduced between the TDG and the protein scaffold maintaining appropriate accessibility for an adequate galectin interaction. The novel conjugates ...

Molecules (Basel, Switzerland), Jan 17, 2018

A series of sp²-iminosugar glycomimetics differing in the reducing or nonreducing character, the ... more A series of sp²-iminosugar glycomimetics differing in the reducing or nonreducing character, the configurational pattern (d- or l-), the architecture of the glycone skeleton, and the nature of the nonglycone substituent has been synthesized and assayed for their inhibition properties towards commercial glycosidases. On the basis of their affinity and selectivity towards GH1 β-glucosidases, reducing and nonreducing bicyclic derivatives having a hydroxylation profile of structural complementarity with d-glucose and incorporating an -octyl-isourea or -isothiourea segment were selected for further evaluation of their inhibitory/chaperoning potential against human glucocerebrosidase (GCase). The 1-deoxynojirimycin (DNJ)-related nonreducing conjugates behaved as stronger GCase inhibitors than the reducing counterparts and exhibited potent chaperoning capabilities in Gaucher fibroblasts hosting the neuronopathic G188S/G183W mutation, the isothiourea derivative being indeed one of the ...

Chemistry (Weinheim an der Bergstrasse, Germany), Jan 2, 2017

Host cell surface carbohydrate receptors of bacterial adhesins are attractive targets in anti-adh... more Host cell surface carbohydrate receptors of bacterial adhesins are attractive targets in anti-adhesion therapy. The affinity of carbohydrate ligands with adhesins is usually found in a low µM range, which poses a problem for the design of effective inhibitors useful in therapy. In an attempt to increase the inhibitory power of carbohydrate ligands, we have combined the approach of chemical modification of ligands with their presentation as multivalent dendrimers in the design of an inhibitor of streptococcal adhesin SadP binding to its galactosyl-α1-4-galactose (galabiose) receptor. Using a phenylurea-modified galabiose-containing trisaccharide in a tetravalent dendrimeric scaffold, inhibition of adhesion at a low picomolar level was achieved. This study is an example of one of a few low picomolar inhibitors observed for bacterial adhesins and demonstrates a promising approach to develop anti-adhesives with the potential of practical applicability.

Chembiochem : a European journal of chemical biology, Sep 29, 2016

Discovery of glycan-competitive galectin-3-binding compounds that attenuate lung fibrosis in a mu... more Discovery of glycan-competitive galectin-3-binding compounds that attenuate lung fibrosis in a murine model and that block intracellular galectin-3 accumulation at damaged vesicles, hence revealing galectin-3-glycan interactions being involved in fibrosis progression and in intracellular galectin-3 activities is reported. Sixteen 3,3´-bis-(4-aryl-triazol-1-yl)-thiodigalactosides were synthesized and evaluated as antagonists of galectin-1, 2, 3, 4 N-terminal, 4 C-terminal, 7, 8 N-terminal, 9 N-terminal, and 9 C-terminal domains. Compounds displaying low-nM affinities for galectin-1 and 3 were identified in a competitive fluorescence anisotropy assay. X-ray structural analysis of selected compounds in complex with galectin-3 and galectin-3 mutant binding experiments revealed that both aryl-triazolyl moieties and fluoro-substituents of the compounds are involved in key interactions responsible for the exceptional affinities for galectin-3. The most potent galectin-3 antagonist was demo...

Organic & Biomolecular Chemistry, 2015

A thiourea spacer adopts an extended conformation and forms the basis of a potent bivalent ligand... more A thiourea spacer adopts an extended conformation and forms the basis of a potent bivalent ligand for Pseudomonas aeruginosa lectin LecA.