Hermen Overkleeft is Professor of Bio-organic Chemistry at the Leiden Institute of Chemistry and has devoted his career to designing molecules to understand and influence disease processes in the human body. His research helps us find new ways to discover novel medicines.

More information about Hermen Overkleeft

Biography

Hermen Overkleeft (1969) is Professor of Bio-organic Chemistry at Leiden University. He studied chemistry at the University of Amsterdam, where he obtained his PhD in 1997 for research on so-called iminosugars: molecules that can inhibit enzymes responsible for breaking down sugars.

After completing his PhD, Overkleeft worked as a postdoctoral researcher in Leiden and subsequently at Harvard Medical School (USA). There, he conducted research on enzymes involved in the immune system. In 2001, he returned to Leiden, where he has since led a research group in bio-organic chemistry.

Research

Overkleeft is both an organic chemist and a chemical biologist. His research focuses on the design of biologically active molecules. Using these molecules, he studies biochemical processes underlying inherited disorders, infectious diseases and cancer. The aim is to understand these processes and to intervene in them.

Overkleeft: ‘We do this by creating molecules in the laboratory that resemble natural molecules, enabling enzymes to recognise them. In our approach, we aim to permanently switch off these enzymes. In this way, we can modulate the biochemical processes that lie at the root of disease.’

An important component of his work is activity-based protein profiling (ABPP): a technique used to detect active enzymes in cells and tissues. His group is internationally recognised as a leader in this field. They have developed new chemical strategies that allow multiple biological processes to be monitored simultaneously. These methods are widely used in biomedical and biotechnological research.

A key theme in his research is the study of enzymes that break down sugars (glycosidases). Malfunctions in these enzymes underlie rare metabolic diseases such as Gaucher disease, Fabry disease and Pompe disease. Probes and inhibitors developed in his laboratory support diagnosis and contribute to the development of new therapies.

His group also investigates enzymes involved in cancer and works on so-called pharmacological chaperones: molecules that can restore the function of defective enzymes.

Collaborations and impact

Overkleeft’s work is fundamental but has clear medical and societal relevance. His group collaborates with researchers both nationally and internationally, particularly in the fields of biochemistry, structural biology and computational chemistry, and has led to the establishment of three start-up companies.

The molecules developed in his laboratory are widely shared with other researchers and form the basis for new research projects and applications, including in biotechnology and drug development.

Honours and awards

Overkleeft has received several international prizes and grants, including:

• Roy L. Whistler International Award in Carbohydrate Chemistry (International Carbohydrate Organization, 2024)
• Jeremy Knowles Award (Royal Society of Chemistry, 2015)
• Wilhelm Friedrich Bessel Award (Alexander von Humboldt Foundation, 2013)
• Gold Medal of the Royal Netherlands Chemical Society (KNCV, 2008)

In 2018, he was elected a member of the Royal Netherlands Academy of Arts and Sciences (KNAW). He has received several major research grants, including an NWO VICI Grant (2003), an ERC Advanced Grant (2011), and an ERC Synergy Grant (2020).

Teaching and supervision

Overkleeft teaches organic chemistry and chemical biology at both undergraduate and postgraduate levels. Over the past decades, he has supervised dozens of PhD candidates and students.

Many of his PhD candidates have won scientific awards and have gone on to hold prominent positions in academia and industry, both in the Netherlands and internationally.

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