TOWARDS THE DESIGN OF STABLE PEPTIDE-LIKE INHIBITORS OF PROTEIN-PROTEIN INTERACTIONS – LARGE SCALE IDENTIFICATION OF “HOT SEGMENTS” IN INTERFACES - ISBE 2015 Conference

Orly Marcu ¹ Yuval Sadan ² Barak Raveh ³ Nir London ⁴ Ora Schueler-Furman ¹

¹Microbiology and Molecular Genetics, Institute for Biomedical Research Israel-Canada (IMRIC), The Hebrew University of Jerusalem, Jerusalem
²Racah Institute of Physics, The Hebrew University of Jerusalem, Jerusalem
³Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco
⁴Department of Organic Chemistry, Weizmann Institute of Science, Rehovot

After years of focus on enzyme inhibition, the drug industry is moving gradually to more fine-tuned manipulation via modulation of specific protein interactions. Can these indeed be inhibited? We have previously developed a simple protocol (PeptiDerive 1 ) that based on a solved protein complex structure identifies short peptide stretches in one of the partners that significantly contribute to binding, and therefore might be used as starting points for inhibitor design.
In order to evaluate the general potential of peptide-based inhibition, we have here applied PeptiDerive 1 to two non-redundant, large sets of interactions extracted from the PROTCID 2 and DOMMINO 3 databases. In our modified version, we identify those peptides that can easily be further stabilized into potent peptidomimetic drugs, including stapling of helices, beta hairpin stabilization of strands, and also cyclization. Our results imply that many interactions can be modified using one of these techniques. Therefore, even though protein-protein interactions have long been described as difficult to target due to their shallow interfaces, our results indicate that peptidomimetics are indeed a promising new venue towards refined tools, and drugs of manipulation of specific interactions.