A comprehensive overview of my publications can be found at ResearcherID and at the School of Chemistry website.

2016

Van de Langemheen, H; Korotkovs, V; Bijl, J; Wilson, C; Kale, SS; Heinis, C; Liskamp, RMJ Polar Hinges as Functionalized Conformational Constraints in (Bi)cyclic Peptides

ChemBioChem 10.1002/cbic.201600612

 
 

 

 

O'Connor, C; Lohan, F; Campos, J; Ohlsson, E; Salome, M; Forde, C; Artschwager, R; Liskamp, RM; Cahill, MR; Kiely, PA; Porse, B; Keeshan, K The presence of C/EBP alpha and its degradation are both required for TRIB2-mediated leukaemia ONCOGENE 2016 35, 5272-5281

DOI: 10.1038/onc.2016.66

 

Brouwer, AJ; Herrero-Alvarez, N; Ciaffoni, A; van de Langemheen, H; Liskamp, RMJ Proteasome inhibition by new dual warhead containing peptido vinyl sulfonyl fluorides BIOORGANIC & MEDICINAL CHEMISTRY 2016 24, 3429-3435

DOI: 10.1016/j.bmc.2016.05.042

 

Postma, TM; Liskamp, RMJ Highly potent antimicrobial peptide derivatives of bovine cateslytin RSC ADVANCES 2016 6, 94840-94844

DOI: 10.1039/c6ra17944d

 
 

 

Postma, TM; Liskamp, RMJ Triple-targeting Gram-negative selective antimicrobial peptides capable of disrupting the cell membrane and lipid A biosynthesis RSC ADVANCES 2016 6, 65418-65421

DOI: 10.1039/c6ra11550k

TOC - RSC Advances.jpg

 

Werkhoven, PR; Elwakiel, M; Meuleman, TJ; Van Ufford, HCQ; Kruijtzer, JAW; Liskamp, RMJ Molecular construction of HIV-gp120 discontinuous epitope mimics by assembly of cyclic peptides on an orthogonal alkyne functionalized TAC-scaffold ORGANIC & BIOMOLECULAR CHEMISTRY 2016 14, 701-710

DOI: 10.1039/c5ob02014j

 
 

 

2015

Slootweg, J. C., Van Herwerden, E.F., Van Doremalen, M. F. M., Breukink, E., Liskamp, R. M. J., Rijkers, D. T. S., Synthesis of nisin AB dicarba analogs using ring-closing metathesis: influence of sp3versus sp2 hybridization of the α-carbon atom of residues dehydrobutyrine-2 and dehydroalanine-5 on the lipid II binding affinity. Org. Biomol. Chem., 2015,13, 5997-6009. DOI: 10.1039/C5OB00336A

Gilfillan, L., Artschwager, R., Harkiss, A. H., Liskamp, R. M. J. Sutherland, A., Synthesis of pyrazole containing α-amino acids via a highly regioselective condensation/aza-Michael reaction of β-aryl α,β-unsaturated ketones Org. Biomol. Chem., 2015,13, 4514-4523 DOI: 10.1039/C5OB00364D

2014

Elgersma, R. C., Kroon-Batenburg, L. M. J., Posthuma, G., Meeldijk, J. D., Rijkers, D. T. S., Liskamp, R. M. J., pH-controlled aggregation polymorphism of amyloidogenic Aβ(16–22): Insights for obtaining peptide tapes and peptide nanotubes, as function of the N-terminal capping moiety. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY (2014)  88  55-65 DOI: 10.1016/j.ejmech.2014.07.089

Tune your tube: the aggregation morphology of the Aβ(16–22) sequence is strongly dependent on the overall charge of the peptide and can be tuned by variations of the N-terminal capping moiety in combination with the pH.

Tune your tube: the aggregation morphology of the Aβ(16–22) sequence is strongly dependent on the overall charge of the peptide and can be tuned by variations of the N-terminal capping moiety in combination with the pH.

Dubiella, C., Cui, H., Gersch, M., Brouwer, A. J., Sieber, S. A., Krüger, A., Liskamp, R. M.J., and Groll, M. (2014) Selective inhibition of the immunoproteasome by ligand-induced crosslinking of the active site. Angewandte Chemie (International Edition), 53(44), pp. 11969-11973. (doi:10.1002/anie.201406964)  (PMID:25244435)

The current benchmark for proteasome inhibition, immunoproteasome inhibitors featuring α′,β′-epoxyketones, were compared to peptido sulfonyl fluorides (PSF) in terms of their mechanism of action, selectivity, and cytotoxicity. PSFs were found to remove the catalytically active nucleophile and then crosslink the active site. Cell-based activity and viability assays designate this warhead for selective immunoproteasome blockage.

The current benchmark for proteasome inhibition, immunoproteasome inhibitors featuring α′,β′-epoxyketones, were compared to peptido sulfonyl fluorides (PSF) in terms of their mechanism of action, selectivity, and cytotoxicity. PSFs were found to remove the catalytically active nucleophile and then crosslink the active site. Cell-based activity and viability assays designate this warhead for selective immunoproteasome blockage.

Harmsen, R. A.G., Ghalit, N., Kemmink, J., Breukink, E., Liskamp, R. M.J., and Rijkers, D. T.S. (2014) A conformationally constrained fused tricyclic nisin AB-ring system mimic toward an improved pyrophosphate binder of lipid II. Tetrahedron, 70(42), pp. 7691-7699.(doi:10.1016/j.tet.2014.06.023)

Liskamp, R. M. J., (2014) Peptides bicycling into cells, Nature Chemistry 6(10), 855-857. (DOI: 10.1038/nchem.2073)

Cleophas, R. T. C., Sjollema, J., Busscher, H. J., Kruijtzer, J. A. W., Liskamp, R. M. J., (2014) Characterization and Activity of an Immobilized Antimicrobial Peptide Containing Bactericidal PEG-Hydrogel, BIOMACROMOLECULES 15(9), 3390-3395. DOI: 10.1021/bm500899r

A single step immobilization-polymerization strategy of a highly active antimicrobial peptide into a soft hydrogel network on a poly(ethylene terephthalate) surface using thiol–ene chemistry is described. The bactericidal hydrogel was molecularly characterized via Coomassie and Lowry assay protein staining agents as well as by X-ray photoelectron spectroscopy. The bactericidal activity was established against Staphylococcus aureus and Staphylococcus epidermidis, two bacterial strains commonly associated with biomaterial infections.

A single step immobilization-polymerization strategy of a highly active antimicrobial peptide into a soft hydrogel network on a poly(ethylene terephthalate) surface using thiol–ene chemistry is described. The bactericidal hydrogel was molecularly characterized via Coomassie and Lowry assay protein staining agents as well as by X-ray photoelectron spectroscopy. The bactericidal activity was established against Staphylococcus aureus and Staphylococcus epidermidis, two bacterial strains commonly associated with biomaterial infections.

An efficient multigram scale synthesis of a new asymmetric triazacyclophane scaffold, the ATAC (Asymmetric-TAC) scaffold, bearing three selectively removable groups is described. This scaffold is slightly more rigid than our frequently used TAC (TriAzaCyclophane) scaffold. The rigidity of the triazacyclophane ring in both TAC- and ATAC scaffolds has also been investigated using variable temperature 1H NMR experiments.

An efficient multigram scale synthesis of a new asymmetric triazacyclophane scaffold, the ATAC (Asymmetric-TAC) scaffold, bearing three selectively removable groups is described. This scaffold is slightly more rigid than our frequently used TAC (TriAzaCyclophane) scaffold. The rigidity of the triazacyclophane ring in both TAC- and ATAC scaffolds has also been investigated using variable temperature 1H NMR experiments.

Brouwer, A. J., van de Langemheen, H., Ciaffoni, A., Schilder, K. E., and Liskamp, R. M.J. (2014) Synthesis of the TACO scaffold as a new selectively deprotectable conformationally restricted triazacyclophane based scaffold. Organic Letters, 16(11), pp. 3106-3109. (doi:10.1021/ol5012218)  (PMID:24856258)

The synthesis of a new triazacyclophane scaffold (TACO scaffold) containing three selectively deprotectable amines is described. The TACO scaffold is conformationally more constrained than our frequently used TAC scaffold, due to introduction of a substituent on the para position of the benzoic acid hinge, which prevents ring flipping and makes it more attractive than the TAC scaffold for preparation of artificial receptor molecules or for mimicking discontinuous epitopes toward protein mimics when more preorganization is required.

The synthesis of a new triazacyclophane scaffold (TACO scaffold) containing three selectively deprotectable amines is described. The TACO scaffold is conformationally more constrained than our frequently used TAC scaffold, due to introduction of a substituent on the para position of the benzoic acid hinge, which prevents ring flipping and makes it more attractive than the TAC scaffold for preparation of artificial receptor molecules or for mimicking discontinuous epitopes toward protein mimics when more preorganization is required.

Cleophas, R. T. C., Riool, M., Van Ufford, H. C. Q. Zaat, S. A. J. Kruijtzer, J. A. W., Liskamp, R. M. J., (2014) Convenient Preparation of Bactericidal Hydrogels by Covalent Attachment of Stabilized Antimicrobial Peptides Using Thiol-ene Click Chemistry, ACS MACRO LETTERS 3(5), 477-480. DOI: 10.1021/mz5001465

This report describes the design and synthesis of a bactericidal poly(ethylene glycol)-based (PEG) hydrogel coating with covalently attached antimicrobial peptides (AMP) stabilized against proteolytic degradation. As such, mimics of the highly active AMP HHC10 (H-KRWWKWIRW-NH2) were designed for optimal stability in human serum while retaining strong antimicrobial activity against Staphylococcus aureus and Staphylococcus epidermidis, the major causative agents of biomaterial associated infection.

This report describes the design and synthesis of a bactericidal poly(ethylene glycol)-based (PEG) hydrogel coating with covalently attached antimicrobial peptides (AMP) stabilized against proteolytic degradation. As such, mimics of the highly active AMP HHC10 (H-KRWWKWIRW-NH2) were designed for optimal stability in human serum while retaining strong antimicrobial activity against Staphylococcus aureus and Staphylococcus epidermidis, the major causative agents of biomaterial associated infection.

González-Ortiz, G., Quarles Van Ufford, H. C., Halkes, S. B. A., Cerdà-Cuéllar, M., Beukelman, C. J., Pieters, R. J., Liskamp, R. M. J., Pérez, J. F., and Martín-Orue, S. M. (2014) New properties of wheat bran: anti-biofilm activity and interference with bacteria quorum-sensing systems. Environmental Microbiology, 16(5), pp. 1346-1353.(doi:10.1111/1462-2920.12441)

van de Langemheen, H., Quarles van Ufford, H. (L.) C., Kruijtzer, J. A. W., and Liskamp, R. M.J. (2014) Efficient synthesis of protein mimics by sequential native chemical ligation. Organic Letters, 16(8), pp. 2138-2141. (doi:10.1021/ol500604h)

Synthetic mimics of protein surfaces have the potential to become inhibitors of protein–protein interactions or even synthetic vaccines. However, the synthesis of these complicated molecular constructs is still difficult. Here we describe an efficient and versatile synthesis of protein mimics containing up to three different cyclic peptides. Using a sequential native chemical ligation strategy, peptide loops containing a thioester handle were introduced onto a triazacyclophane scaffold bearing orthogonal protected cysteine residues.

Synthetic mimics of protein surfaces have the potential to become inhibitors of protein–protein interactions or even synthetic vaccines. However, the synthesis of these complicated molecular constructs is still difficult. Here we describe an efficient and versatile synthesis of protein mimics containing up to three different cyclic peptides. Using a sequential native chemical ligation strategy, peptide loops containing a thioester handle were introduced onto a triazacyclophane scaffold bearing orthogonal protected cysteine residues.

Using an orthogonally protected three alkyne derivative of the triazacyclophane scaffold, three different azido functionalized cyclic peptides were introduced successively affording a discontinuous epitope mimic of the pertactin protein of Bordetella pertussis in a convergent way.

Using an orthogonally protected three alkyne derivative of the triazacyclophane scaffold, three different azido functionalized cyclic peptides were introduced successively affording a discontinuous epitope mimic of the pertactin protein of Bordetella pertussis in a convergent way.

A novel strategy to prepare bisubstrate based inhibitors for histone acetyltransferases is presented. To obtain these, azido peptides derived from histone H3 incorporating either a serine or a phosphoserine residue were connected to a propargyl coenzyme A derivative through copper catalyzed click chemistry. The resulting inhibitors were tested with therapeutically relevant acetyltransferase PCAF. Increased potency of the phosphoserine containing inhibitor was observed. The synthetic strategy presented may be used for developing bisubstrate based inhibitors against any acetyltransferase.

A novel strategy to prepare bisubstrate based inhibitors for histone acetyltransferases is presented. To obtain these, azido peptides derived from histone H3 incorporating either a serine or a phosphoserine residue were connected to a propargyl coenzyme A derivative through copper catalyzed click chemistry. The resulting inhibitors were tested with therapeutically relevant acetyltransferase PCAF. Increased potency of the phosphoserine containing inhibitor was observed. The synthetic strategy presented may be used for developing bisubstrate based inhibitors against any acetyltransferase.

van de Langemheen, H., van Hoeke, M., Quarles van Ufford, H.C., Kruijtzer, J.A.W., and Liskamp, R.M.J. (2014) Scaffolded multiple cyclic peptide libraries for protein mimics by native chemical ligation. Organic and Biomolecular Chemistry, 12(25), pp. 4471-4478.(doi:10.1039/c4ob00190g)  (PMID:24849139)

The accessibility to collections, libraries and arrays of cyclic peptides is increasingly important since cyclic peptides may provide better mimics of the loop-like structures ubiquitously present in and – especially – on the surface of proteins. The next important step is the preparation of libraries of ensembles of scaffolded cyclic peptides, which upon screening may lead to promising protein mimics. Here we describe the synthesis of a tri-cysteine containing scaffold as well as the simultaneous native chemical ligation of three cyclic peptides thereby affording a clean library of multiple cyclic peptides on this scaffold, representing potential mimics of gp120. Members of this collection of protein mimics showed a decent inhibition of the gp120-CD4 interaction.

The accessibility to collections, libraries and arrays of cyclic peptides is increasingly important since cyclic peptides may provide better mimics of the loop-like structures ubiquitously present in and – especially – on the surface of proteins. The next important step is the preparation of libraries of ensembles of scaffolded cyclic peptides, which upon screening may lead to promising protein mimics. Here we describe the synthesis of a tri-cysteine containing scaffold as well as the simultaneous native chemical ligation of three cyclic peptides thereby affording a clean library of multiple cyclic peptides on this scaffold, representing potential mimics of gp120. Members of this collection of protein mimics showed a decent inhibition of the gp120-CD4 interaction.

van der Wal, S., Capicciotti, C. J., Rontogianni, S., Ben, R. N., and Liskamp, R. M.J. (2014) Synthesis and evaluation of linear CuAAC-oligomerized antifreeze neo-glycopeptides. MedChemComm, 5(8), pp. 1159-1165. (doi:10.1039/c4md00013g)

Antifreeze glycoproteins (AFGPs) are important naturally occurring biological antifreezes that lower the freezing point of a solution, thereby preventing uncontrolled ice growth. These compounds also inhibit ice recrystallization. Described in this paper is a synthetic antifreeze glycopeptide-based polymer synthesized from an azide/alkyne glycopeptide building block by partial reduction of the azide and subsequent copper catalyzed azide alkyne cycloaddition (CuAAC) polymerization to obtain linear oligomers.

Antifreeze glycoproteins (AFGPs) are important naturally occurring biological antifreezes that lower the freezing point of a solution, thereby preventing uncontrolled ice growth. These compounds also inhibit ice recrystallization. Described in this paper is a synthetic antifreeze glycopeptide-based polymer synthesized from an azide/alkyne glycopeptide building block by partial reduction of the azide and subsequent copper catalyzed azide alkyne cycloaddition (CuAAC) polymerization to obtain linear oligomers.

2013

Slootweg, J. C., van der Wal, S., Quarles van Ufford, H. C., Breukink, E., Liskamp, R. M. J., and Rijkers, D. T. S. (2013) Synthesis, antimicrobial activity, and membrane permeabilizing properties of C-terminally modified nisin conjugates accessed by CuAAC.Bioconjugate Chemistry, 24(12), pp. 2058-2066.(doi:10.1021/bc400401k)

A convenient method is reported for the synthesis of nisin conjugates and it is shown that these nisin derivatives retain both their antimicrobial activity and their membrane permeabilizing properties. The synthesis is based on the Cu(I)-catalyzed alkyne–azide cycloaddition reaction (CuAAC) as a bioorthogonal ligation method for large and unprotected peptides in which nisin was C-terminally modified with propargylamine and subsequently efficiently conjugated to a series of functionalized azides. Two fluorescently labeled nisin conjugates together with a dimeric nisin construct were prepared while membrane insertion as well as antimicrobial activity were unaffected by these modifications.

A convenient method is reported for the synthesis of nisin conjugates and it is shown that these nisin derivatives retain both their antimicrobial activity and their membrane permeabilizing properties. The synthesis is based on the Cu(I)-catalyzed alkyne–azide cycloaddition reaction (CuAAC) as a bioorthogonal ligation method for large and unprotected peptides in which nisin was C-terminally modified with propargylamine and subsequently efficiently conjugated to a series of functionalized azides. Two fluorescently labeled nisin conjugates together with a dimeric nisin construct were prepared while membrane insertion as well as antimicrobial activity were unaffected by these modifications.

The synthesis, structural characterization, and synthetic use as an advanced intermediate is described of a cross-stapled alkene-bridged hexapeptide to mimic the DE-ring of the lantibiotic nisin. The linear precursor was cyclized by ring-closing metathesis to give the correctly folded bicyclic hexapeptide in a single step, and the four individual diastereoisomers were isolated, structurally assigned and characterized by HPLC, NMR and MS, respectively. The bicyclic hexapeptide was used as a versatile advanced synthon and was modified at its C- and N-terminus, among others, with an azide moiety to access a building block suitable for Cu(I)-catalyzed alkyne–azide cycloaddition-based ligation reactions.

The synthesis, structural characterization, and synthetic use as an advanced intermediate is described of a cross-stapled alkene-bridged hexapeptide to mimic the DE-ring of the lantibiotic nisin. The linear precursor was cyclized by ring-closing metathesis to give the correctly folded bicyclic hexapeptide in a single step, and the four individual diastereoisomers were isolated, structurally assigned and characterized by HPLC, NMR and MS, respectively. The bicyclic hexapeptide was used as a versatile advanced synthon and was modified at its C- and N-terminus, among others, with an azide moiety to access a building block suitable for Cu(I)-catalyzed alkyne–azide cycloaddition-based ligation reactions.

The activity of important protein tyrosine phosphatases has been monitored in real time in parallel with a novel substrate microarray through formation of 3-nitrotyrosine

The activity of important protein tyrosine phosphatases has been monitored in real time in parallel with a novel substrate microarray through formation of 3-nitrotyrosine

Tschan, S. Brouwer, A. J., Werkhoven, P.R., Jonker, A. M., Wagner, L., Knittel, S., Aminake, M. N., Pradel, G., Joanny, F., Liskamp, R. M. J., Mordmuller, B, (2013) Broad-spectrum antimalarial activity of peptido sulfonyl fluorides, a new class of proteasome inhibitors.Antimicrobial Agents and Chemotherapy, 57(8), pp. 3576-3584.(doi:10.1128/AAC.00742-12)

van Wandelen, L. T. M., van Ameijde, J., Ismail-Ali, A. F., van Ufford, H. C. (L.) Q., Vijftigschild, L. A. W., Beekman, J. M., Martin, N. I., Ruijtenbeek, R., and Liskamp, R. M. J. (2013) Cell-penetrating bisubstrate-based protein kinase C inhibitors. ACS Chemical Biology, 8(7), pp. 1479-1487. (doi:10.1021/cb300709g)

 
Although protein kinase inhibitors present excellent pharmaceutical opportunities, lack of selectivity and associated therapeutic side effects are common. Bisubstrate-based inhibitors targeting both the high-selectivity peptide substrate binding groove and the high-affinity ATP pocket address this. However, they are typically large and polar, hampering cellular uptake. This paper describes a modular development approach for bisubstrate-based kinase inhibitors furnished with cell-penetrating moieties and demonstrates their cellular uptake and intracellular activity against protein kinase C (PKC). This enzyme family is a longstanding pharmaceutical target involved in cancer, immunological disorders, and neurodegenerative diseases. However, selectivity is particularly difficult to achieve because of homology among family members and with several related kinases, making PKC an excellent proving ground for bisubstrate-based inhibitors. Besides the pharmacological potential of the novel cell-penetrating constructs, the modular strategy described here may be used for discovering selective, cell-penetrating kinase inhibitors against any kinase and may increase adoption and therapeutic application of this promising inhibitor class.

Although protein kinase inhibitors present excellent pharmaceutical opportunities, lack of selectivity and associated therapeutic side effects are common. Bisubstrate-based inhibitors targeting both the high-selectivity peptide substrate binding groove and the high-affinity ATP pocket address this. However, they are typically large and polar, hampering cellular uptake. This paper describes a modular development approach for bisubstrate-based kinase inhibitors furnished with cell-penetrating moieties and demonstrates their cellular uptake and intracellular activity against protein kinase C (PKC). This enzyme family is a longstanding pharmaceutical target involved in cancer, immunological disorders, and neurodegenerative diseases. However, selectivity is particularly difficult to achieve because of homology among family members and with several related kinases, making PKC an excellent proving ground for bisubstrate-based inhibitors. Besides the pharmacological potential of the novel cell-penetrating constructs, the modular strategy described here may be used for discovering selective, cell-penetrating kinase inhibitors against any kinase and may increase adoption and therapeutic application of this promising inhibitor class.

 

Slootweg, J. C., van Schaik, T. B., Quarles van Ufford, H. (L.) C., Breukink, E., Liskamp, R. M. J., and Rijkers, D. T.S. (2013) Improving the biological activity of the antimicrobial peptide anoplin by membrane anchoring through a lipophilic amino acid derivative.Bioorganic and Medicinal Chemistry Letters, 23(13), pp. 3749-3752.(doi:10.1016/j.bmcl.2013.05.002)

Zhang, J., Kemmink, J., Rijkers, D. T. S., and Liskamp, R. M. J. (2013)Synthesis of 1,5-triazole bridged vancomycin CDE-ring bicyclic mimics using RuAAC macrocyclization. Chemical Communications, 49(40), pp. 4498-4500. (doi:10.1039/c3cc40628h)

Mulder, G. E., Quarles van Ufford, H. (L.). C., van Ameijde, J., Brouwer, A. J., Kruijtzer, J. A. W., and Liskamp, R. M. J. (2013)Scaffold optimization in discontinuous epitope containing protein mimics of gp120 using smart libraries. Organic and Biomolecular Chemistry, 11(16), pp. 2676-2684. (doi:10.1039/c3ob27470e)

Vosyka, O., Vinothkumar, K.R., Wolf, E.V., Brouwer, A.J., Liskamp, R.M.J., and Verhelst, S.H.L. (2013) Activity-based probes for rhomboid proteases discovered in a mass spectrometry-based assay.Proceedings of the National Academy of Sciences of the United States of America, 110(7), pp. 2472-2477. (doi:10.1073/pnas.1215076110)

Nuijens, T., Schepers, A.H.M., Cusan, C., Kruijtzer, J.A.W., Rijkers, D.T.S., Liskamp, R.M.J., and Quaedflieg, P.J.L.M. (2013) Enzymatic fragment condensation of side chain-protected peptides using subtilisin A in anhydrous organic solvents: a general strategy for industrial peptide synthesis. Advanced Synthesis & Catalysis, 355(2-3), pp. 287-293. (doi:10.1002/adsc.201200694)

de Mol, N.J., Kruijtzer, J.A.W., Moret, E.E., Broutin, I., and Liskamp, R.M.J. (2013) Unusual binding of Grb2 protein to a bivalent polyproline-ligand immobilized on a SPR sensor: intermolecular bivalent binding. Biochimica et Biophysica Acta: Proteins and Proteomics, 1834(2), pp. 524-535. (doi:10.1016/j.bbapap.2012.11.001)

Werkhoven, P. R., and Liskamp, R. M.J. (2013) Chemical approaches for localization, characterization and mimicry of peptide epitopes.In: Jones, L. H. and McKnight, A. J. (eds.) Biotherapeutics: Recent Developments using Chemical and Molecular Biology. Series: RSC Drug Discovery Series (36). The Royal Society of Chemistry: Cambridge, pp. 263-284. ISBN 9781849736015 (doi:10.1039/9781849737159)