Transitioning novel peptide hits into lead compounds

Developing novel peptide hits into lead compounds can be challenging and requires a modified approach compared to small molecules. When screening for hits on difficult drug targets such as orphan G-protein coupled receptors (GPCRs) or ion channels it is often necessary to go outside of the Lipinski rule of five. These compounds are in libraries which could include natural products, peptides, fragments etc. Finding the hit is the first step, and this then may be used as a tool to rescreen small molecules libraries with better confidence. But often this new hit needs to be investigated as potential lead material to progress the project from a potentially stalled situation. Unlike synthetic compound libraries, natural product hits need to be identified and then characterised as the actual molecule is often unknown. Peptide libraries come from a range of sources and they all have limitations and benefits. Venom peptides are often inherently stable due to cysteine knots whereas other peptides may not be. This article will take on the challenges of the hit-to-lead journey with these non-standard hits.