Chemical Biology is the discipline in which fundamental biological processes are studied by approaches intrinsically rooted in chemistry. The research of Herman Overkleeft is characterized by the design, synthesis and application of chemical probes in glycobiology and immunology.

More information about Hermen Overkleeft

Biography

Herman Overkleeft obtained his PhD degree in 1997 under the guidance of Professor Upendra Pandit (University of Amsterdam) on the subject of iminosugars as glycosidase inhibitors. He then did post-doctoral research with Professor Jacques van Boom (Leiden University, the Netherlands, 1997-1999) on ring-closing metathesis in the synthesis of polyhydroxylated oxacycles and azacycles, and with Professor Hidde Ploegh (Harvard Medical School, Boston, CA, USA, 1999-2001) on inhibition of proteases involved in human adaptive immunity. He returned to the Netherlands in 2001 to assume his current chair of bioorganic chemistry at Leiden University.
Herman Overkleeft is an organic chemist and chemical biologist whose activity-based protein profiling (ABPP) program (Acc Chem Res 2011, 718) is recognized as leading internationally. His lab was the first (coinciding with the Cravatt group) to connect ABPP with bioorthogonal chemistry (van Swieten, Angew Chem Int Ed 2003) and the first to perform three bioorthogonal reactions in a single experiment (Willems, Angew Chem Int Ed 2012). His lab developed a chemoselective linker for chemical proteomics profiling (Geurink, Angew Chem Int Ed, 2009), and lysosomal cysteine protease (cathepsin) ABPs targeted to cells through the mannose receptor (Hillaert, Angew Chem Int Ed, 2010) and the M6P receptor (Hoogendoorn, Angew Chem Int Ed, 2014). The developed inhibitors and activity-based probes are highly sought-after commodities both for application in biomedicine and biotechnology studies. This has led to numerous fruitful collaborations, and to weekly shipments of compounds without strings attached to interested colleagues.

A main focus throughout the years has been the development of inhibitors and activity-based probes for human constitutive proteasomes and immunoproteasomes. This has resulted in a unique set of reagents and tools with which each of the six catalytic activities of the human constitutive proteasome and immunoproteasome combined can be inhibited and visualized (van Swieten, Angew Chem Int Ed 2003; de Bruin, Angew Chem Int Ed 2016; de Bruin, J Am Chem Soc 2016). Key collaborators on proteasome research are Alexei Kisselev (Auburn University, Alabama, USA; biochemistry, enzymology), Michael Groll (Technical University Munich, Germany; enzymology, structural biology) and Christoph Driessen (St Gallen Medical Centre, Switzerland; onco-haematology).

Since 2010, major efforts in the lab are devoted to the design, synthesis and application of activity-based probes (ABPs) for retaining exoglycosidases, the deficiency of which is at the basis of various lysosomal storage disorders. Based on the natural product, cyclophellitol, ABPs have been designed that are specific for lysosomal glucosylceramidase (Witte, Nat Chem Biol 2010 – diagnostic tools for Gaucher disease), for retaining β-glucosidases in general (Kallemeijn, Angew Chem Int Ed 2014), retaining α-galactosidases (Willems, J Am Chem Soc 2014 – diagnostic tools for Fabry disease), retaining α-fucosidases (Jiang, Chem Sci 2015), retaining α-glucosidase probes (Jiang, ACS Cent Sci 2016 – diagnostic tools for Pompe disease), retaining β-glucuronidases (Wu, Nat Chem Biol 2017 – diagnostic probes for human heparanase), retaining -L-arabinofuranosidases (McGregor J Am Chem Soc 2020) and xylanases (Schröder, ACS Cent Sci 2019 – diagnostic tools for enzyme activity under harsh industrial biotechnological conditions). Alongside activity-based glycosidase probes, the laboratory has amassed over the years a focused library of over 400 iminosugars as inhibitors of glycosidases and glycosyl transferases (Wennekes, J Med Chem 2010; Ghisaidoobe, J Med Chem 2014); which are used in competitive ABPP assays for the discovery of new glycosidase inhibitors for further medicinal chemistry elaboration (Lahav, J Am Chem Soc 2017; Armstrong, J Am Chem Soc 2020). Key collaborators in glycobiology are Hans Aerts (Leiden University, The Netherlands; medical biochemistry), Gideon Davies (University of York, UK; structural biology) and Carme Rovira (University of Barcelona, Spain; computational chemistry).

The chemical biology research of Overkleeft is of a fundamental nature, yet with a strong focus on finding new molecules for drug discovery. His glycosidase inhibitors and probes form the basis for current research programs on the discovery of human heparanase inhibitors and Golgi mannosidase inhibitors (cancer) as well as pharmacological chaperones for human lysosomal alpha-glucosidase (Pompe disease) and alpha-galactosidase (Fabry disease). 

Herman Overkleeft is the recipient of a Wilhelm Friedrich Bessel Award from the Alexander Humboldt Society (Germany, 2013), the ‘Gouden Medaille’ (Gold Medal, best Dutch <40 Years chemist) from the Royal Dutch Chemical Society (KNCV, 2008), of the 2015 Jeremy Knowles Award from the Royal Chemical Society (RSC, UK), and was elected (2018) member of the Royal Dutch Academy of Arts and Sciences (KNAW). Amongst the research grants he received are an NWO VICI grant (2003), an ERC Advanced Grant (2012) and, jointly with Carme Rovira and Gideon Davies, an ERC Synergy Grant (2020).
 

Curriculum Vitae

Personal information

Nationality:   Netherlands
Date of birth:   12 April 1969

Education

1997   PhD, Faculty of Chemistry, University of Amsterdam, The Netherlands, 14 March 1997
Thesis title: ‘Azasugars. Synthesis and evaluation as glycosidase inhibitors’
Advisor: Prof. Dr. U.K. Pandit
1992   MSc in Chemistry, Faculty of Chemistry, University of Amsterdam, The Netherlands

Current and previous research positions

2001 – now     Full Professor in Bioorganic Chemistry, Leiden Institute of Chemistry, Leiden University, The Netherlands
1999 – 2001   Post-doctoral Researcher, Department of Pathology, Harvard Medical School, Boston, MA, USA, supported by an NWO fellowship (Prof. H.L. Ploegh)
1997 – 1999   Post-doctoral Researcher, Leiden Institute of Chemistry, Leiden University, The Netherlands (Prof. J.H. van Boom)

Grants, awards, recognitions since 2010

2023   EU Doctoral Network ‘Glyco-N’ (co-applicant, main applicant Antonio Molinaro, k€ 540, 3 years)
2023   EU ERC Proof of Concept Grant HEPARANIB (main applicant; k€150, 18 months
2022   NWO Take-Off Grant (k€ 40, 6 months) for establishing iProtics as a Biotech start-up company
2020   ERC Synergy Grant CARBOCENTRE (lead PI, co-PIs Carme Rovira and Gideon Davies, M€ 3.7 - total grant amount M€ 9.1, 6 years)
2020   Kezar Life Sciences Research Grant (k€ 50, 6 months)
2019   Kezar Life Sciences Research Grant (k€ 180, 1 year)
2018   NWO TOP Grant (main applicant; co-applicants Jeroen Codée and Hans Aerts, k€ 823, 5 years).
2018   Elected member, Royal Dutch Academy of Sciences and Arts (KNAW)
2016   NWO Building Blocks of Life Grant with J.M.F.G. Aerts and J.J.C. Neefjes (k€ 800)
2016   Appointed Fellow of the Royal Society of Chemistry (FRSC), United Kingdom
2016   Visiting Professor at Orleans University, France
2015   Jeremy Knowles Award, Royal Society of Chemistry, United Kingdom
2015   EU ERC Proof of Concept Grant (k€ 150)
2014   NWO-CW TOP-PUNT grant with J.M.F.G. Aerts and H. Ovaa (k€ 2.000)
2013   Dutch Ministry of Education Gravitation Grant (co-applicant with J. Neefjes, P. Gros, A. Heck, C. Figdor, T. Schumacher) for the Institute of Chemical Immunology (M€ 27.6 Euro formally split over the six applicants, 10 years)
2013   EU Innovative Medicines Initiative: European Lead Factory with M. van der Stelt (k€ 829)
2013   Visiting Professor at the Technical University Berlin, Germany
2012   NWO Graduate School Grant for the Netherlands Graduate School in Chemical Biology (main applicant, k€ 800 divided equally between Leiden University, Radboud University, Groningen, University and Technical University Eindhoven)
2012   Friedrich Wilhelm Bessel Research Award, Alexander von Humboldt Foundation, Germany
2011   ZonMw Zenith grant (k€ 400)
2011   NWO-CW ChemThem Chemical Biology Grant with J.M.F.G. Aerts (k€ 500)
2011   EU ERC Advanced Grant with J.M.F.G. Aerts (k€ 3,000)
2011   ZonMw TOP Grant, main applicant F. Ossendorp (LUMC), (co-applicant k€ 237)
2011   EU-COST Action (chair)
2011   NWO-CW TA-COAST grant (k€ 164)
2011   STW grant, main applicant A.J.M. Driessen (co-applicant k€ 145)
2010   NWO-CW ECHO grant (k€ 260)
2010   BMM/CTMM/TI Pharma Grant, co-applicant; main applicant F. Ossendorp (LUMC) (k€ 336)

Contribution to teaching and supervision

• One course for BSc Molecular Science and Technology (Leiden/Delft): Biomolecular Chemistry
• One course for MSc Chemistry at Leiden University: Chemical Biology

Herman Overkleeft has in the past 20 years taught both elementary (Bachelor) and advanced (Master) courses in synthetic organic chemistry. He developed and taught to first-year bachelor students Molecular Science & Technology (MST), Life Science & Technology (LST) and Biopharmaceutical Sciences (BFW) an introduction course in general chemistry, and a third year Bachelor course (MST) in Biomolecular Chemistry and a Master course in Chemical Biology. He guided the Bachelor- and Master Thesis research of multiple students.

He acted as Thesis supervisor of over 40 former PhD students (37 since 2008) and is currently (October 2023) Thesis supervisor of ten PhD students. Dr Ovaa (2001), Dr Grotenbreg (2005), Dr Witte (2009), Dr Geurink (2010), Dr Walvoort (2012), Dr Willems (2014), Dr Hoogendoorn (2014) and Dr de Bruin (2016) received their PhD degree with the distinction ‘Cum Laude’ (awarded to the top-3% PhD students at Leiden University). Dr Bonger (PhD 2008) was granted the ‘Best Thesis in Pharmacology 2009’ award. Dr Wennekes (PhD 2008) was granted the ‘Best Thesis in Medicinal Chemistry 2008-2009’ award. Dr Witte (PhD 2010), Dr Walvoort (PhD 2012) and Dr Willems (PhD 2014) were granted the ‘Best Thesis in Organic Chemistry’ award of their year. Dr Ovaa (PhD 2001) was Professor in Chemical Biology at the Leiden University Medical Centre. Dr Timmer (PhD 2005) is Lecturer in Immunoglycomics at the Victoria University of Wellington, New Zealand. Dr Wennekes (PhD 2009) is Associate Professor at Utrecht University (NL). Dr Witte (PhD 2010) and Dr Walvoort (PhD 2012) are Associate and Assistant Professor, respectively, at Groningen University (NL), Dr Bonger (PhD 2010) and Dr Verdoes (PhD 2010) are Associate Professor at the Radboud University Nijmegen (NL), Dr Risseeuw (PhD 2009) holds a research staff position at Ghent University (BE). Dr Li (PhD 2013) and Dr Jiang (PhD 2016) are Assistant Professor at Shenzen University (CH), Dr Willems (PhD 2014) is Lecturer at the University of York (UK), and Dr Hoogendoorn (PhD 2014) is Assistant Professor at Geneva University (SUI). Many former PhD students have attracted prestigious personal grants of their own as exemplified by ERC Starting Grants for Dr Verdoes (2015), Dr Bonger (2018), Dr Willems (2019) and Dr Hoogendoorn (2020). Virtually all his former PhD students are active in chemistry, with many working in the private sector, both in start-up biotech companies and in established chemical industry, in the Netherlands and abroad.

Other responsibilities since 2010

• Editorial Board member of Carbohydrate Research (since 2012). Editorial Advisory Board member of the European Journal of Organic Chemistry (since 2008), ChemBioChem (since 2010) and Bioorganic Medicinal Chemistry (since 2015)
• Member of review panels for the Netherlands Organisation for Scientific Research (NWO), Deutsche Forschungsgemeinschaft (DFG), and the Finnish Academy of Sciences
• External member to PhD committees in Germany, Italy and Denmark
• Reviewer for Science, Nature Methods, Nature Chemical Biology, Nature Protocols, Nature Communications, Angewandte Chemie, Journal of the American Chemical Society, Cell Chemical Biology, Chemical Science and various organic chemistry, bioorganic chemistry, medicinal chemistry and chemical biology journals
• Member of the management board of the Institute of Chemical Immunology (2013 - present), of the Topsector Chemistry ‘Chemistry for Life’ program board (2014 - present) and of the management board of the Netherlands proteomics Centre (2008 - 2013)
• Chair of the selection committee of the KNCV ‘Gouden Medaille’ award committee (2012 - present) and of the NWO Chemical Sciences study group ‘Design and Synthesis’ (2007 - 2011)

Publication record including five recent representative publications

~605 papers and book chapters with ~20000 citations, H-index 68 (Web of Science)

Full publication record: Leiden University

• H. Ovaa, P.F. van Swieten, B.M. Kessler, M.A. Leeuwenburgh, E. Fiebiger, A.M.C.H. van den Nieuwendijk, P.J. Galardy, G.A. van der Marel, H.L. Ploegh and H.S. Overkleeft, Chemistry in living cells: detection of active proteasomes by a two-step labeling strategy, Angew. Chem. Int. Ed. 2003, 42, 3626-3629. DOI: 10.1002/anie.200351314
  This paper represents the first example, together with work from the Cravatt group (J. Am. Chem. Soc. 2003, 125, 16, 4686–4687) merging activity-based protein profiling and bioorthogonal chemistry.
• M.D. Witte, W.W. Kallemeijn, J. Aten, K.-Y. Li, A. Strijland, W.E. Donker-Koopman, B. Blijlevens, G. Kramer, A.M.C.H. van den Nieuwendijk, B.I. Florea, B. Hooibrink, C.E.M. Hollak, R. Ottenhoff, R.G. Boot, G.A. van der Marel, H.S. Overkleeft and J.M.F.G. Aerts, Ultrasensitive in situ visualization of active glucocerebrosidase molecules, Nat. Chem. Biol. 2010, 6, 907-913. DOI: 10.1038/nchembio.466
  Introducing the use of modified derivatives of the natural product, cyclophellitol, in activity-based glycosidase profiling.
• L.I. Willems, N. Li, B.I. Florea, M. Ruben, G.A. van der Marel and H.S. Overkleeft, Triple bioorthogonal ligation strategy for simultaneous labeling of multiple enzymatic activities, Angew. Chem. Int. Ed. 2012, 51, 4431-4434. DOI: 10.1002/anie.201200923
  The first example of a triplicate bioorthogonal strategy to visualize three biological processes independently in a single experiment.    
• A.T. Ghisaidoobe, R.J.B.H.N. van den Berg, S.S. Butt, A. Strijland, W.E. Donker-Koopman, S. Scheij, A.M.C.H. van den Nieuwendijk, G.-J. Koomen, A. van Loevezijn, M. Leemhuis, T. Wennekes, M. van der Stelt, G.A. van der Marel, C.A.A. van Boeckel, J.M.F.G. Aerts and H. S. Overkleeft, Identification and development of biphenyl substituted iminosugars as improved dual glucosylceramide synthase/neutral glucosylceramidase inhibitors, J. Med. Chem. 2014, 57, 9096-9104. DOI: 10.1021/jm501181z
  Introducing lipophilic iminosugars as dual inhibitors of glucosylceramide synthesis and cytosolic glucosylceramide breakdown and containing the compounds licensed by Azafaros for development towards clinical trials (www.azafaros.com).
• J. Jiang, C.-L. Kuo, L. Wu, C. Franke, W.W. Kallemeijn, B.I. Florea, E. van Meel, G.A. van der Marel, J.D.C. Codée, R.G. Boot, G.J. Davies, H.S. Overkleeft and J.M.F.G. Aerts, Detection of active mammalian GH31 alpha-glucosidases in health and disease using in-class, broad-spectrum activity-based probes, ACS Cent. Sci. 2016, 2, 351-358. DOI: 10.1021/acscentsci.6b00057
  Expanding the cyclophellitol-based activity-based glycosidase profiling technology towards the enzyme deficient in Pompe disease: lysosomal alpha-glucosidase. The technology has since then been expanded to numerous retaining exo-and endoglycosidases.
• L. Wu, J. Jiang, Y. Jin, W.W. Kallemeijn, C.-L. Kuo, M. Artola, W. Dai, C. van Elk, M. van Eijk, G.A. van der Marel, J.D.C. Codée, B.I. Florea, J.M.F.G. Aerts, H.S. Overkleeft and G.J. Davies, Activity-based probes for functional interrogation of retaining beta-glucuronidases, Nat. Chem. Biol. 2017, 13, 867-873. DOI: 10.1038/nchembio.2395
  The discovery of the first potent small-molecule inhibitor of the prospective anticancer target, heparanase.
• M. Artola, L. Wu, M.J. Ferraz, C.-L. Kuo, L. Raich, I.Z. Breen, W.A. Offen, J.D.C. Codée, G.A. van der Marel, C. Rovira, J.M.F.G. Aerts, G.J. Davies and H.S. Overkleeft, 1,6-Cyclophellitol cyclosulfates: a new class of irreversible glycosidase inhibitor, ACS Cent. Sci. 2017, 3, 784-793. DOI: 10.1021/acscentsci.7b00214
  The design of the first Michaelis complex emulating potent and selective covalent and irreversible retaining glycosidase inhibitor.
• D. Lahav, B. Liu, R.J.B.H.N. van den Berg, A.M.C.H. van den Nieuwendijk, T. Wennekes, A.T. Ghisaidoobe, I. Breen, M.J. Ferraz, C.-L. Kuo, L. Wu, P.P. Geurink, H. Ovaa, G.A. van der Marel, M. van der Stelt, R.G. Boot, G.J. Davies, J.M.F.G. Aerts and H.S. Overkleeft, A fluorescence polarization activity-based protein profiling assay in the discovery of potent, selective inhibitors for human non-lysosomal glucosylceramidase, J. Am. Chem. Soc. 2017, 139, 14192-14197. DOI: 10.1021/jacs.7b07352
  The design of an efficient inhibitor screening methodology based on activity-based glycosidase profiling.
• S.P. Schröder, C. de Boer, N.G.S. McGregor, R.J. Rowland, O. Moroz, E. Blagova, J. Reijngoud, M. Arentshorst, D. Osborn, M.D. Morant, E. Abbate, M.A. Stringer, K.B.R.M. Krogh, L. Raich, C. Rovira, J.-G. Berrin, G.P. van Wezel, A.F.J. Ram, B.I. Florea, G.A. van der Marel, J.D.C. Codée, K.S. Wilson, L. Wu, G.J. Davies and H.S. Overkleeft, Dynamic and functional profiling of xylan-degrading enzymes in Aspergillus secretomes using activity-based probes, ACS Cent. Sci. 2019, 5, 1067-1078. DOI: 10.1021/acscentsci.9b00221
  The first potent and selective retaining endoglycosidase profiling reagent, expanding the application of ABPP to the field of biotechnology: the discovery of glycohydrolases for the sustainable turnover of biomass polysaccharides.
• N. McGregor, M. Artola, A. Nin-Hill, D. Linzel, M. Haon, J. Reijngoud, A.F.J. Ram, M.-N. Rosso, G.A. van der Marel, J.D.C. Codée, G.P. van Wezel, J.-G. Berrin, C. Rovira, H.S. Overkleeft and G. J. Davies, Rational design of mechanism-based inhibitors and activity-based probes for the identification of retaining α-L-arabinofuranosidases, J. Am. Chem. Soc. 2020, 142, 4648-4662. DOI: 10.1021/jacs.9b11351
  Expanding the ABPP technology from pyranosidases to furanosidases, as demonstrated on alpha-L-arabinofuranosidases that are widely sought after for the turnover of biomass polysaccharides.​​​​​​​

Publications