Method of developing small molecule peptide conjugates for biomedical applications

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This application provides a platform design wherein a substrate peptide of the protein-protein interaction complex is tagged with a variety of small molecule fragments using amide chemistry. The method of hit discovery coupled with subsequent amide-mediated rapid diversification for lead generation reduces time and cost to discovery and development of target specific small molecule leads for the inhibition of protein-protein interactions.

Protein-protein interaction (PPI) drug targets are notoriously hard to target due to their broad and relatively featureless binding sites. They are often termed as the ‘high hanging fruits’ or the ‘undruggable’ targets in drug discovery. Enormous efforts towards the low hanging fruits or easier to target drug targets have reached a saturation point. There is emerging interest in newer technologies that enable rapid identification of high-quality and diverse chemical starting points for PPI inhibitor development. Traditional small molecule screening techniques like high throughput screening often identifies large and complex molecules with undesirable physicochemical properties especially in the case of PPI drug targets. These hits are usually non-specific weak binders and require extensive medicinal chemistry efforts to improve their potency and drug-like properties. Traditional fragment based drug design (FBDD) in hit discovery has been successful against easier drug targets like kinases and hydrolases. However, the FBDD approach in PPI drug discovery has been extremely challenging, as the identification of weak moderately binding small molecule fragments to broad PPI binding sites is difficult.

Smith et al provide design of small molecule-peptide conjugates. However, this study does not design a library of such conjugates, and use the entire conjugate as a drug/small molecule, which makes it a peptidomimetic approach.

US20110118126 provides a method for screening a compound that binds to a target wherein a bait fragment with a preselected bait moiety is reacted with multiple fragments to form small molecule ligands. Herein, a method of identifying an optimal hit molecule by rapidly screening large number of chemical molecules after binding the molecule to the target protein by sulfide bond is described.

The present invention is a novel platform technology referred herein as the ‘Smip’ Platform, which employs in silico high throughput screening of small molecule fragments against a protein-peptide/protein-protein target of interest, while attached to the interacting peptide via an amide bond. This results in the generation of a library of small molecule peptide conjugates(SMPC). The top docked SMPC hits are selected and synthesized. The SMPC hits are then screened against the target of interest using traditional biochemical assays. Following SMPC hit identification, the small molecule fragments attached to best SMPC hits is further evolved into a small molecule lead/inhibitor against the target of interest.

The high throughput screening format ensures the exploration of a wide chemical space while significantly reducing the time and cost of screening when compared to traditional fragment based screening technologies. Also the facile diversification of the initial small molecule hits by replacement of the peptide with amine-terminated fragments will reduce the burden on medicinal chemistry for the generation of lead.