Intracellular protein-protein-interactions (PPIs) represent a wide class of potential drug targets across several important disease areas such as cancer, infectious diseases, auto-immunity and diabetes. The discovery of small molecules (<500 daltons MW) to inhibit these interactions for therapeutic treatment have on the whole proven to be challenging to conventional approaches. Antibodies and peptides constitute modalities that are much more efficient at disrupting PPIs than small molecules, as they have the capacity to form much larger interaction interfaces with their target molecules. However, these larger molecular weight entities, unlike small molecules which can usually be designed to be diffuse rapidly across the mammalian cell membrane, are not innately cell membrane permeable. To address this issue many innovative approaches have been taken ranging from development of new chemically constrained macrocyclic entities to the design of delivery systems than can enable the intracellular penetration of impermeable cargo e.g. antibodies and mini-proteins. However achieving cellular permeability rapidly and rationally has proved elusive. In the absence of known cell permeable inhibitors against a large number of intracellular PPIs, there is an increasing need to develop alternative methodologies to validate these interfaces as targets for therapeutic development before initiating costly and time intensive programs to develop cell permeable macrocylics. To address this objective we have developed the Peptide Epitope Loop Exchange system (PELE), whereby the macrocyclic motif critical for binding to the target is grafted or evolved on to a suitable mini-protein (< 15000 MW) and then matured for optimal binding. The PELE system has enabled the discovery of several novel proteins that can be expressed easily within cells or used in animal models to model the potential action of the desired final compound under development. Several examples pertaining to modelling of alternative therapeutic inhibition strategies of cap dependent translation (eIF4F) will be described.