Anders Bach

• February 2009-: Postdoc, Dept. of Med. Chem. (Prof. Strømgaard)
• February 2009: Ph.D. (Medicinal Chemistry), Dept. of Med. Chem. (Prof. Strømgaard)
• March 2005: M.Sc. (Human Biology)
• June 2002: B.Sc. (Biochemistry)

In this project we focus on a protein domain family named PDZ. These domains are highly abundant in the human proteome and participate in several therapeutical relevant protein-protein interactions. PSD-95 is a scaffold protein that interacts with the NMDA receptor through its PDZ domains and thereby involved in excitoxicity (Figure). We have used peptidomimetic approaches to develop potent and biological active PSD-95 inhibitors, such as N-alkylated tetrapeptides and dimeric ligands, and also worked with small molecules to gain new insight into the field.

1. Bach, A.*; Clausen, B. H.; Møller, M.; Vestergaard, B.; Chi, C. N.; Round, A.; Sørensen, P. L.; Nissen, K. B.; Kastrup, J. S.; Gajhede, M.; Jemth, P.; Kristensen, A. S.; Lundström, P.; Lambertsen, K. L.; Strømgaard, K.*. A high-affinity, dimeric inhibitor of PSD-95 bivalently interacts with PDZ1-2 and protects against ischemic brain damage. Proc. Natl. Acad. Sci. U. S. A. 2012, 109, 3317-3322. (*Corresponding authors).

2. Haq, S. R.; Chi, C. N.; Bach, A.; Dogan, J.; Engström, Å.; Hultqvist, G.; Karlsson, O. A.; Lundström, P.; Montemiglio, L. C.; Strømgaard, K.; Gianni, S.; Jemth, P. Side-chain interactions form late and cooperatively in the binding reaction between disordered peptides and PDZ domains. J. Am. Chem. Soc. 2012, 134, 599-605.

3. Thorsen, T. S.; Madsen K. L.; Dyhring, T.; Bach, A.; Peters, D.; Strømgaard, K.; Rønn, L. C.; Gether, U. A fluorescence polarization based screening assay for identification of small molecule inhibitors of the PICK1 PDZ domain. Comb. Chem. High Throughput Screen. 2011, 14, 590-600.

4. Sivertsen, B.; Lang, M.; Frimurer, T. M.; Holliday, N. D.; Bach, A.; Els, S.; Engelstoft, M. S.; Petersen, P. S.; Schwartz, T. W.; Beck-Sickinger, A. G.; Holst, B. Unique interaction pattern of a functionally biased ghrelin receptor agonist. J. Biol. Chem. 2011, 286, 20845-20860.

5. Bach, A.; Eildal, J. N. N.; Stuhr-Hansen, N.; Deeskamp, R.; Gottschalk, M.; Pedersen, S. W.; Kristensen, A., S.; Strømgaard, K.. Cell-permeable and plasma-stable peptidomimetic inhibitors of the postsynaptic density-95/N-methyl-D-aspartate receptor interaction. J. Med. Chem. 2011, 54, 1333-1346.

6. Bach, A.; Strømgaard, K. Expedient synthesis of 1,3-substituted benzene peptidomimetics. Synthesis 2011, 807-815.

7. Chi, C. N.; Bach, A.; Engström, A.; Strømgaard, K.; Lundström, P.; Ferguson, N.; Jemth, P. Biophysical characterization of the complex between human papillomavirus E6 protein and synapse associated protein 97. J. Biol. Chem. 2011, 286, 3597-3606.

8. Bach, A.; Stuhr-Hansen, N.; Thorsen, T. S.; Bork, N.; Moreira, I.; Frydenvang, K.; Padrah, S.; Brøgger Christensen, S.; Madsen, K. L.; Weinstein, H.; Gether, U.; Strømgaard, K. Structure-activity relationships of a small-molecule inhibitor of the PDZ domain of protein interacting with Cα-kinase 1. Org. Biomol. Chem. 2010, 8, 4281-4288.

9. Chi, C. N.; Bach, A.; Gottschalk, M.; Kristensen, A. S.; Strømgaard, K.; Jemth, P. Deciphering the kinetic binding mechanism of dimeric ligands, using a potent plasma-stable dimeric inhibitor of postsynaptic density protein-95 as an example. J. Biol. Chem. 2010, 285, 28252-28260.

10. Thorsen, T. S.; Madsen, K. L.; Rebola, N.; Bach, A.; Moreira, I.; Peters, D.; Dyhring, T.; Beuming, T.; Weinstein, H. A; Strømgaard, K.; Mulle, C.; Rønn, B. L.-C.; Gether, U. Identification of a small molecule inhibitor of the PICK1 PDZ domain that inhibits hippocampal LTP and LTD. Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 413-418.

11. Holst, B.; Nygaard, R.; Valentin-Hansen, L.; Bach, A.; Engelstoft, M. S., Petersen, P. S.; Frimurer, T. M.; Schwartz, T. W. A conserved aromatic lock for the tryptophan rotameric switch in TM-VI of 7TM receptors. J. Biol. Chem. 2010, 285, 3973-3985.

12. Bach, A.; Chi, C. N.; Pang, G. F.; Olsen, L.; Kristensen, A. S.; Jemth, P.; Strømgaard, K. Design and synthesis of highly potent and plasma-stable dimeric inhibitors of the PSD-95/NMDA receptor interaction. Angew. Chem. Int. Ed. 2009, 48, 9685-9689.

13. Chi, C. N.; Bach, A.; Engström, Å.; Wang, H., Strømgaard, K.; Gianni, S.; Jemth, P. A sequential binding mechanism in a PDZ domain. Biochemistry 2009, 48, 7089-7097. 

14. Gottschalk, M.; Bach, A.; Hansen, J. L.; Krogsgaard-Larsen, P.; Kristensen, A.S.; Strømgaard, K. Detecting protein-protein interactions in living cells: Development of a bioluminescence resonance energy transfer (BRET) assay to evaluate the PSD-95/NMDA receptor interaction. Neurochem. Res. 2009, 34, 1729-1737.

15. Bach, A.; Chi, C. N.; Olsen, T. B.; Pedersen, S. W.; Røder, M. U.; Pang, G. F.; Clausen, R. P.;Jemth, P.; Strømgaard, K. Modified peptides as potent inhibitors of the postsynaptic density-95/N-methyl-D-aspartate receptor interaction. J. Med. Chem. 2008, 51, 6450-6459.

16. Holst, B.; Lang, M.; Brandt, E.; Bach, A.; Howard, A.; Frimurer, T. M.; Beck-Sickinger, A.; Schwartz, T. W. Ghrelin receptor inverse agonists: identification of an active peptide core and its interaction epitopes on the receptor. Mol. Pharmacol. 2006, 70, 936-946.

17. Holst, B.; Brandt, E.; Bach, A.; Heding, A.; Schwartz, T. W. Nonpeptide and peptide growth hormone secretagogues act both as ghrelin receptor agonist and as positive or negative allosteric modulators of ghrelin signaling. Mol. Endocrinol. 2005, 19, 2400-2411.

18. Holst, B.; Holliday, N. D.; Bach, A.; Elling, C. E.; Cox, H. M.; Schwartz, T. W. Common structural basis for constitutive activity of the ghrelin receptor family. J. Biol. Chem. 2004, 279, 53806-53817.

1. Bach, A.; Strømgaard, K. EP 11165994.2, US 61/485898, 2011.

2. Bach, A.; Strømgaard, K. PCT WO2010/004003, 2010.

1. Exploratory Pre-seed Grant, Novo Nordisk Foundation: DKK 500.000 (2012)

2. The Carlsberg Foundation: DKK 525.000 (2012) (Postdoc salary for one year)

3. The Novo Nordisk Foundation: DKK 400.000 (2011)

4. The Danish Agency for Science, Technology and Innovation (Proof of Concept Foundation): DKK 750.000 (2011)

5. The Danish Agency for Science, Technology and Innovation (Proof of Concept Foundation): DKK 750.000 (2010)

6. Familien Hede Nielsens Foundation: DKK 25.000 (2010)

7. Direktør Ib Henriksens Foundation: DKK 50.000 (2010)

8. The Danish Council for Independent Research (Technology and Production Sciences): DKK 2 mill. (2010) (Postdoc salary for two years)

Danish Society of Pharmacology, Toxicology, and Medicinal Chemistry (DSFTM): Young Danish Scientist 2010

Bach, A.; Gottschalk, M.; Kristensen, A. S.; Strømgaard, K. Protein-protein interaktioner – et nyt mål for udvikling af lægemidler, Lægemiddelforskningen 2008.

1. Oral communication at the European Federation for Medicinal Chemistry’s International Symposium on Medicinal Chemistry (EFMC-ISMC), September 2008, Vienna, Austria.

2. Oral communication at the annual meeting of Danish Society of Pharmacology, Toxicology, and Medicinal Chemistry (DSFTM), May 2008, Copenhagen, Denmark.