A Chemical Library Approach to Organic-Modified Peptide Ligands for PDZ Domain Proteins: A Synthetic, Thermodynamic and Structural Investigation

✍ Scribed by D. Gomika Udugamasooriya; Sudhir C. Sharma; Mark R. Spaller

• Publisher: John Wiley and Sons
• Year: 2008
• Tongue: English
• Weight: 444 KB
• Volume: 9
• Category: Article
• ISSN: 1439-4227
• DOI: 10.1002/cbic.200800126

✦ Synopsis

PDZ domains are members of the protein interaction domain family, [1] semi-autonomous modules embedded within larger signaling proteins that impart a degree of exclusivity to the binding properties of their hosts. As mediators of mammalian protein-protein interactions that number in the hundreds, PDZ domains are party to a correspondingly large array of cellular processes, most notably those that regulate or support neuronal activities. [2] Specific, bioavailable molecular probes are needed to foster biological inquiries into their functions; towards this end, we report our recent progress in the discovery and development of PDZ domain inhibitors.

Here the focus is on the protein postsynaptic density 95 (PSD-95), which bears three PDZ domains. Abundant in neurons, PSD-95 serves as a nexus for transient interactions that affect core synaptic events, such as transmission and plasticity. [3,4] Inhibitors that selectively uncouple these PDZ domainpromoted associations will greatly assist in determining their exact roles. Further, disrupting these interactions of PSD-95 could constitute novel therapeutic avenues for treatment of stroke and ischemic brain damage [5] and other excitotoxic disorders. [6] We now expand upon prior work in which linear peptide ligands for the third PDZ domain (PDZ3) of PSD-95 were developed. [7] Data from that investigation, in conjunction with an Xray crystal structure we solved of PDZ3 bound to the hexapeptide KKETWV (PDB ID: 1TP5), indicate that the binding site occupied by the side chain of the penultimate C-terminal residue (Figure 1, position P À1 ) can accommodate a variety of organic substructures. We hypothesized that suitable elaboration of a side chain within that site-and perhaps even just beyond its perimeter-might enhance existing interactions and possibly accrue new ones.

A ligand design strategy was devised, built upon a parallel chemical synthesis platform, in which a diverse collection of A C H T U N G T R E N N U N G organic acids was used to acylate individually an amino side chain at P À1 of a peptide ligand for PDZ3 (Scheme 1). This approach was inspired by a library-based peptide modification protocol, in which consensus sequences have been iteratively transformed into high-affinity ligands. [8] As originally reported, however, the methodology does not allow for display and screening of the unmodified peptide C terminus (a strict re-[a] D.