Interfering with Protein-Protein Contact: Molecular Interaction Maps and Peptide Modulators

Abstract

Protein-protein interactions (PPIs) can be useful targets for different pathologies. In fact controlling a function or attempting to repair an anomaly often means interfering with the cross-talk among different proteins. In order to have a general view of these cross-talks, Molecular Interaction Maps (MIMs) are used, organizing the enormous available information that is added every day and trying to understand the most suitable and accurate targets for any specific cell alteration. In this paper the c-Myc protein is taken as an example to explain the use of a map. The discovery of a peptidomimetic antagonist of c-Myc, active against proliferation of cancer cell lines, is reported and a possible mechanism of action is explained. To interfere with a specific protein-protein contact, a good starting point can be to consider a protein entity. Because the interaction between two proteins is normally characterized by a wide zone of contact, relative large inhibitors could be more convenient in the first approaches. Therefore, peptides mimicking the interacting zone can be considered as potential leads in the rational design of effective molecules. Here different examples of peptides as protein-protein interaction inhibitors are reported.

Discovery of a Class of Diketopiperazines as Antiprion Compounds

“…In inhibiting protein-protein interactions, peptides mimicking the interacting zone have been considered as relevant starting points in the rational design of effective molecules. [26] Similarly, peptidomimetics have become effective modulators of a range of biologically significant protein-protein interactions [27] by orienting their side-chain substituents in a spatially defined manner. Furthermore, these compounds are stable to proteolysis and consequently possess better drug-like properties than peptides.…”

Jatropha cultivation in southern India: assessing farmers' experiences

“…Therefore, in our search of novel bifunctional molecules, we looked for a spacer that might have an active role in the molecular‐recognition process. In inhibiting protein–protein interactions, peptides mimicking the interacting zone have been considered as relevant starting points in the rational design of effective molecules 26. Similarly, peptidomimetics have become effective modulators of a range of biologically significant protein–protein interactions27 by orienting their side‐chain substituents in a spatially defined manner.…”

Motif mediated protein-protein interactions as drug targets

“…The transient nature of these interactions, moderate affinity, promiscuity of recognition, and binding interface structural properties, are among the many factors that have contributed to difficulty in discovering effective inhibitors. This had led to a general sense that protein–protein interactions might not be amenable to inhibition by small molecules [ 3 , 27 – 32 ]. A perhaps instructive counterpoint to this view is the case of protein kinases: They were also considered to be challenging to target until a few decades ago.…”

“…2 ). Increasing size involves new challenges, for instance the rise of the entropic penalty to bind (less potential to reach lower affinities) [ 33 , 48 ] as well as poor cell delivery [ 3 , 28 , 30 – 32 ].

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“…Success was partially due to the fact that successfully inhibited interactions are domain-motif interactions, and the resulting molecule was mimicking the peptide motif. Thus through a considerable efforts in in medical chemistry and careful structural considerations, a high affinity binder was generated [ 30 – 32 ].…”