Bioinspired Protein Hybrids

Our design is inspired by key principles that engineer life such as programmed assembly, precision chemistry and ordered structures, to derive a new class of protein hybrid materials that surpass their native components. We seek to translate our competency in synthetic chemistry to develop versatile platforms for protein modifications that are complementary to recombinant technologies. In this way, a new generation of structurally precise protein hybrids which are evolved beyond their innate functions can be prepared to address current challenges for biomedical applications such as new administration routes, formulations with higher efficacy or programming stimuli responsiveness. 

 

1. Bioactive Peptide Conjugates
   
   The peptide hormone somatostatin (SST) can serve both as a targeting ligand as well as an antiproliferative drug and their conjugates are of immense clinical interest for radiotherapy, tumor imaging and chemotherapy. Using a disulfide rebridging strategy, various bioactive SST conjugates were prepared that exhibit synergistic properties of SST and the synthetic entities.
   
   
   
   
2. Multidomain Protein Complexes
   About 70-80 % of proteins found in Nature exists permanently as oligomers and multipartite complexes with precise spatial orientation and play significant roles in biological functions. For instance, bacterial toxins are highly optimized toolbox which offers structurally distinct protein domains exhibiting remarkable cell type selectivity and domains that affect intracellular signaling processes. We have developed various strategies to prepare biohybrids with defined macromolecular architectures to emulate Nature. Notably, the protein hybrids are installed with additional features beyond their innate functions.

• Core-shell Albumin Nanotransporters 
  
  Human serum albumin is a natural transporter for various molecules and one of the most exploited proteins used as a drug delivery vehicle in therapeutics and clinical biochemistry. HSA possesses hydrophobic pockets to which fatty acids and drugs can bind and also offer various possibilities with many functional groups that are accessible on the hydrophilic surface of the molecule to introduce additional attractive features such as enhanced loading or cell uptake. Here, we developed several strategies to introduce a cell-penetrating shell around the protein core to enhance its uptake features. The biohybrids not only exhibit properties from both the biological and chemical entities but also are non-toxic and can incorporate a higher loading of drugs.
  
  
  
• Supramolecular Fusion Proteins
  The streamlined design of toxins have prompted us to explore various non-covalent strategies for the bottom-up assembly of multipartite protein complexes. Although recombinant technologies allow the fusion of two protein domains genetically, it is limited by loss of activity, excludes combination of chemically post-modified proteins and cannot incorporate pH- or photo-switches. We have developed a solid phase approach which can serve as a complementary tool for (a) the delivery of stimuli-responsive fusion proteins and (2) to reprogram therapeutically attractive proteins such as redirecting cell entry of toxins for biomedical applications.
  
  

 

Dr. Markus Lamla (Senior Scientist)
Dr. Wang Tao (Postdoc)
Marco Raabe (Masters)

Past members

Dr. Jessica Thomas (PhD)
Pascal Heitel (Masters)
Diana Moura (Eramus) 
Anne Blank (Bachelor) 
Marco Raabe (Bachelor) 
Alexander Mengele (Bachelor)
Achim Keidel (Bachelor)
Konstantin Schneider-Heieck (Bachelor)

Professional Experience

Since 1/2013 Group Leader (Bio-inspired Organic Chemistry)

Institute of Organic Chemistry III, Ulm University, Germany

2011-2012 Alexander von Humboldt Fellow

Institute of Organic Chemistry III, Ulm University, Germany

Max Planck Institute for Polymer Research, Mainz, Germany

2010 Scientist

Health Sciences Authority Singapore, Singapore

2008-2010 Research Fellow

Department of Chemistry, National University of Singapore, Singapore

2004-2008 Teaching Assistant

Department of Chemistry, National University of Singapore, Singapore

2002-2008 Mentor

Special Programme in Science, National University of Singapore, Singapore

Education

2004-2008 PhD, Chemistry

Department of Chemistry, National University of Singapore, Singapore

1999-2003 BSc(Hons), Chemistry

Department of Chemistry, National University of Singapore, Singapore

Awards

2011-2012 Alexander von Humboldt Fellowship

Alexander von Humboldt Foundation, Germany

2004-2008 NUS Nanoscience and Nanotechnology Initiative Graduate Scholarship

National University of Singapore, Singapore

1. T. Wang, A. Riegger, M. Lamla, S. Wiese, P. Oeckl, M. Otto, Y. Wu, S. Fischer, H. Barth, S. L. Kuan, T. Weil. Water-Soluble Allyl Sulfones for Dual Site-Specific Labelling of Proteins and Cyclic Peptides. Chemical Science (2016), 7, 3234-3239.
2. S. L. Kuan, C. Foertsch, D. Y. W. Ng, S. Fischer, Y. Tokura, W. Liu, Y. Wu, K. Koynov, H. Barth*, T. Weil*. A Supramolecular Approach towards Bioinspired PAMAM-Dendronized Fusion Toxins. Macromolecular Biosciece. (2016),16, 803-10.
3. Y. Wu, D. Y. W. Ng, S. L. Kuan, T. Weil*. Protein-Polymer Therapeutics – A Macromolecular Perspective. Biomater. Sci. (2015), 3, 214-230.
4. S.L. Kuan*, T. Wang, M. Raabe, W. Liu, M. Lamla, T. Weil*. Programming Bioactive Architectures with Cyclic Peptide Amphiphiles. ChemPlusChem (2015), 80, 1347–1353.  (VIP)
5. D. Y. W. Ng, Y. Wu, S. L. Kuan, T. Weil. Programming Supramolecular Biohybrids as Precision Therapeutics. Acc. Chem. Res. (2014), 47, 3471-3480.
6. Y. Wu, C. Li, F. Boldt, C. Förtsch, S. L. Kuan, D. Liu*, T. Weil*, et. al. Precise Assembly of Proteins into Hydrogel: A Multifunctional Protein-DNA Hybrid Hydrogel for Application and Controlled Release of Therapeutic Proteins and Use as Growth Matrix for 3D Cell Culture. Chem. Commun. (2014), 50, 14620-14622.
7. C. Y. Ang, S. L. Kuan, G. K. Tan, L. Y. Goh, T. L. Roemmele, X. Yu and R. T. Boeré. Coordination complexes of thiazyl rings. Synthesis, structure and DFT computational analysis of CpCr(CO)x (x = 2,3) complexes of fluorinated and non-fluorinated λ3-1,2,4,6-thiatriazinyls, with differing Cr—S bond orders. Canadian Journal of Chemistry (2014),  10.1139/cjc-2014-0257.
8. T. Wang, Y. Wu, S. L. Kuan, O. Dumele, M. Lamla, D. Y. W. Ng, M. Arzt, J. Thomas, J. O. Müller, C. Barner-Kowollik, T. Weil*. A Disulfide Intercalator Toolbox for the Site-Directed Modification of Polypeptides.# Chem. Eur. J. (2014), 21, 228–238.
   #Hot Paper
9. R. Stangenberg, Y. Wu, J. Hedrich, D. Kurzbach, D. Wehner, G. Weidinger, S. L. Kuan, M. I. Jansen, F. Jelezko, H. J. Luhmann, D. Hinderberger, T. Weil*, K. Müllen*.  A Polyphenylene Dendrimer Drug Transporter with Precisely Positioned Amphiphilic Surface Patches. Adv. Healthc. Mater. (2014), 4, 377–384.
10. D. Y. W. Ng, M. Arzt, Y. Wu, S. L. Kuan, M. Lamla, T. Weil*.  Constructing Hybrid Protein Zymogens through Protective Dendritic Assembly. Angew. Chem. Int. Ed. (2014), 53, 324–328.
11. R. Stangenberg, I. Saeed, S. L. Kuan, M. Baumgarten, T. Weil, M. Klapper, K. Müllen*. Tuning Polarity of Polyphenylene Dendrimers by Patched Surface Amphiphilicity—Precise Control over Size, Shape, and Polarity. Macromol. Rapid Commun. (2013),  35, 152-160.
12. S. L. Kuan, D. Y. W. Ng, Y. Wu, C. Förtsch, H. Barth, M. Doroshenko, K. Koynov, C. Meier, T. Weil*. pH Responsive Janus-like Supramolecular Fusion Proteins for Functional Protein Delivery. J. Am. Chem. Soc. (2013), 135, 17254–17257.
13. J. Hedrich, Y. Wu, S. L. Kuan, F. Kuehn, E. Pietrowski, M. Sahl, S. Muth, K. Müllen, H. J. Luhmann*, T. Weil*, M. Schmidt. Polymer Complexes in Biological Applications. Adv. Polym. Sci. (2013). doi: 10.1007/12_2013_229
14. D. Y. W. Ng, J. Fahrer, K. Eisele, S. L. Kuan, H. Barth, T. Weil*. Efficient Delivery of p53 and Cytochrome C by Supramolecular Assembly of a Dendritic Multi-Domain Delivery System. Adv. Healthcare Mater. (2013), 2, 1620-1629.
15. T. Wang, A. Pfisterer, S. L. Kuan, Y. Wu, O. Dumele, M. Lamla, K. Müllen, T. Weil*. Cross-Conjugation of DNA, Proteins and Peptides via the pH Switch. Chemical Science. (2013), 4, 1889-1894
16. S. L. Kuan, Y. Wu,  T. Weil*. Precision Biopolymers from Protein Precursors for Biomedical Applications. Feature Article in Macromol. Rapid. Comm. (2013), 34, 380-392.
17. Y. Wu,  S. Ihme, M. Feuring-Buske, S. L. Kuan, K. Eisele, M. Lamla, Y. Wang, C. Buske, T. Weil*. Tailored albumin copolymers for high capacity loading and two-step release of doxorubicin with enhanced anti-leukemia activity. Adv. Healthcare Mater. (2013), 2, 884–894.
18. S. L. Kuan, B. Stöckle, J. Reichenwallner,  D. Y. W. Ng,  Y. Wu, M. Doroshenko, K. Koynov, D. Hinderberger, K. Müllen, T. Weil*. Dendronized Albumin Core-Shell Transporters with High Drug Loading Capacity. Biomacromolecule (2013), 14, 367-376.
19. S. L. Kuan, W. K. Leong, R. D. Webster, L. Y. Goh*. Mixed-sandwich (Cp*/(HMB))Ru Complexes Containing bis(methimazolyl)(pyrazolyl)borate. Organometallics (2012), 31 (14), 5159–5168.
20. S. L. Kuan, W. K. Leong, R. D. Webster, L. Y. Goh*. Mixed‐Sandwich Cp*Cr Complexes Containing Poly(methimazolyl)borates (Cp* = C5Me5): Syntheses and Structural and Electrochemical Studies. Organometallics (2012), 31 (1), 273–281.
21. Y. Wu, S. Chakrabortty, R. A. Gropeanu, J. Wilhelmi, Y.  Xu, K. S. Er, S. L. Kuan, Y. T. Chan, T.  Weil*. pH‐Responsive Quantum Dots via an Albumin‐Polymer Surface Coating. J. Am. Chem. Soc. (2010), 132 (14), 5012–5014.
22. H. F. Lau, P. C. Y.  Ang, V. W. L. Ng, S. L. Kuan, L. Y. Goh*, S. A. Borisov, P. Hazendonk, T. L. Roemmele, R. T. Boere*, R. D. Webster. Coupling of CpCr(CO)3 and Heterocyclic Dithiadiazolyl Radicals. Synthetic, X‐ray Diffraction, Dynamic NMR, EPR, CV, and DFT Studies. Inorg. Chem. (2008), 47(2), 632‐644.
23. R. T. Boere, L. Y. Goh, P. C. Y.  Ang, S. L. Kuan, H. F. Lau, V. W. L. Ng, T. L. Roemmele, S. D. Seagrave. A tert‐butyl/cyano substituted (1,2,3,5‐dithiadiazolyl)benzene and h2 p complexes with CpCr(CO)2. J. Organomet. Chem. (2007), 692(13), 2697‐2704.
24. E. P. L. Tay, S. L. Kuan, W. K. Leong, L. Y. Goh. Synthetic and x‐ray Structural and Reactivity Studies of Cp*RuIV Complexes Containing Bidentate Dithiocarbonate, Xanthate, Carbonate, and Phosphinate Ligands (Cp = h5‐C5Me5). Inorg. Chem. (2007), 46(4), 1440‐1450.
25. P. C. Y.  Ang, Boere, R. T. Boere*, L. Y. Goh*, L. L. Koh, S. L. Kuan, G. K. Tan, X. Yu. h1 and h2 complexes of l3‐1,2,4,6‐thiatriazinyls with CpCr(CO)x. Chem. Commun. (2006), 45, 4735‐4737.
26. S. L. Kuan, E. P. L. Tay,  W. K. Leong, L. Y. Goh*, C. Y. Lin, P. M. W. Gill, R. D. Webster*. Highly Oxidized Ruthenium Organometallic Compounds. The Synthesis and One‐Electron Electrochemical Oxidation of [Cp*RuIVCl2(S2CR)] (Cp* = h5‐C5Me5, R = NMe2, NEt2, OiPr). Organometallics (2006), 25(26), 6134‐6141.
27. S. L. Kuan, W. K. Leong*, L. Y. Goh*, R. D. Webster.  HMB and Cp* ruthenium(II) complexes containing bis‐ and tris‐(mercaptomethimazolyl)borate ligands: Synthetic, x‐ray structural and electrochemical studies (HMB = h6‐C6Me6, Cp* = h5‐C5Me5). J. Organomet. Chem. (2006), 691(5), 907‐915.
28. S. L. Kuan, W. K. Leong, L. Y. Goh*, R. D. Webster*.  Redox‐Dependent Isomerization of Organometallic RuII/RuIII Compounds Containing the Hydrotris(methimazolyl)borate Ligand: An Electrochemical Square Scheme Mechanism. Organometallics (2005), 24(19), 4639‐4648.
29. V. W. L. Ng, S. L. Kuan, W. K. Leong, L. L. Koh, G. K. Tan, L. Y. Goh*, R. D. Webster. Heterocyclic Thionates as a New Class of Bridging Ligands in Oxo‐Centered Triangular Cyclopentadienylchromium(III) Complexes. Inorg. Chem. (2005), 44(15), 5229‐5240
30. V. W. L. Ng, S. L. Kuan, Z. Weng, W. K. Leong, J. J. Vittal, L. L. Koh, G. K. Tan, L. Y. Goh*. Reactivity of [CpCr(CO)3]2 towards thione (C:S) moieties in some sulfur‐containing substrates. J. Organomet. Chem. (2005), 690(9), 2323‐2332.
31. X. L. Lu, J. J. Vittal, E. R. T. Tiekink, G. K. Tan, S. L. Kuan, L. Y. Goh*, T. S. A. Hor*. Comparative reactivity studies of dppf‐containing CpRuII and (C6Me6)RuII complexes towards different donor ligands (dppf = 1,1'‐bis(diphenylphosphino)ferrocene). J. Organomet. Chem. (2004), 689(11), 1978‐1990.