Protein-protein interactions (PPIs) are essential to vital cellular processes, and serve as potential targets for therapeutic intervention. We are particularly interested in the PPIs between integral membrane proteins and their intracellular protein partners, and examine how modulation of such PPIs can provide novel biological insight. We have developed peptide-based inhibitors of the PSD-95/glutamate receptor interaction, by exploiting that PSD-95 contains a tandem PDZ1-2 domain. So we designed and synthesized dimeric peptides with low nanomolar affinities, and have demonstrated that these ligands are potential treatment for ischemic stroke. For the same PPI, we examined the importance of backbone hydrogen bond by employing amide-to-ester mutations in peptide ligands and proteins. Similarly, we have exploited the principle of dimeric peptide-based ligands to perturb the PPI between the scaffolding protein gephyrin and glycine/GABAA receptors. Most recently we have developed high affinity, cell-permeable peptides and demonstrated how these can modulate inhibitory receptors and used to label synapses. We have used peptide microarrays to more systematically examine receptor/gephyrin interactions, which combined with pull down and mass spectrometry have provided insights into gephyrin protein networks. Finally, we have explored cyclic depsipeptide natural products as potent and selective inhibitors of specific G proteins. First by developing a synthetic methodology to generate these compounds and subsequently by performing structure-activity relation studies.