Lars Baltzer
Uppsala University, Sweden
Title: Increasing affinity and selectivity for target proteins by peptide conjugation to small molecule ligands – extending interactions “just†outside of the binding pocket
Biography
Biography: Lars Baltzer
Abstract
Organic synthesis has reached a level of proficiency that allows the efficient preparation of molecules of high complexity but the design of small organic molecules and peptides with sufficient affinities and selectivities for proteins in biomedical applications lags behind. We have developed a technology where polypeptide conjugation to small organic molecules or peptides provides affinities increased by as much as four orders of magnitude in comparison to those of the small molecules. Selectivities between highly homologous proteins, measured as ratios of dissociation constants, have been shown to increase by between one and two orders of magnitude. The aspect of the technology that appears to be the most surprising, while it at the same time makes it the most attractive to use, is that a single sixteen membered set of polypeptides is enough to improve affinities and selectivities for essentially any protein. We have recently begun to focus our attention on problems related to in vivo applications, addressing a) the risk of elicitation of immune responses and b) the problem of fast renal clearance. To this end, chemical modifications were introduced that allowed us to reduce the size of the polypeptides from the original 42-residue scaffolds to 11-mers without loss of affinity. We have identified a small molecule ligand that will provide tight binding of peptides to human serum albumin, a carrier protein present in human blood at a concentration of 0.6 mM. HSA binding will keep peptides in circulation thus reducing the problem of fast renal clearance and, in addition, the rate of proteolytic degradation. The peptide conjugates to be discussed may be used e.g. in clinical imaging or as radiotherapeutic agents, but also as guides for the redesign of small molecule drugs or for target validation purposes.
Illustration of concept. Conjugate formed from small molecule ligand and 42-residue polypeptide binds target protein due to small molecule-protein interactions supplemented by those between peptide and protein in close proximity to the small molecule binding site. Protein is human Carbonic Anhydrase II and small molecule ligand is benzenesulphonamide.