Targeting Protein-Protein Interactions For Drug Discovery

Heat shock protein 70kDa (HSP70), ATPase fragment. Image Courtesy the European Bioinformatics Institute

Cambridge Healthtech Institute (CHI) organizes the annual Drug Discovery Chemistry (DDC) conference that focuses on drug discovery of small molecule candidates and challenges involved in their optimization. True to its motto ?Optimizing Small Molecules For Tomorrow?s Therapeutics?, the DDC meeting that was held in San Diego from April 23-25, 2014 focused on multiple drug discovery platforms.

Small molecule drug discovery aims to treat clinical diseases by targeting specific molecules involved in the disease pathway(s). One of the most important targets for drug discovery is protein-protein interaction (PPI). PPIs are associated with a wide range of functions depending on the protein partners involved in the interaction. If two transcription factors interact, this usually leads to DNA binding and subsequent effects on transcription. On the other hand, proteins such as kinases interact and affect downstream signaling. Based on their roles in different diseases, multiple PPIs can be attractive therapeutic targets. The best PPIs for targeting are identified by examining evidence of the biological function in diseases to be addressed.

In spite of their potential as promising targets, PPIs are considered to be ?undruggable? or difficult to target. The main reason is that PPI have a high-efficiency binding region for different partners of the protomer. These so-called hotspots may involve large surface areas and may be dictated by multiple different physico-chemical forces that make it difficult to target.

The 7th Annual Protein-Protein Interactions meeting at DDC discussed ways to overcome these limitations and demonstrated promising small molecule inhibitors of PPIs. The chairperson for this meeting, Jason E. Gestwicki, PhD from UC San Francisco introduced the area by describing how chemical biology was being used to develop drugs in the nineties and how the field has developed and matured since then. Further, in his talk, Gestwicki discussed different screening strategies for targeting PPIs, including tethering, fragment-based drug design, structure-based design, and computational modeling-driven drug design. It is important to note that of the various strategies discussed, some PPIs may be more amenable to specific strategies that need to be explored. Gestwicki specifically focused on targeting PPI to inhibit the Heat Shock Protein 90 (Hsp70) complex.

In the same session, Lee Fader from Boehringer Ingelheim Pharmaceuticals talked about allosteric modulators of PPIs with the aim of inhibiting HIV replication. An important step in replication of the virus is capsid assembly. Allosteric inhibitors of capsid assembly have been developed that are being tested for further activity.

Laura Silvian, PhD from Biogen Idec tackled ways to disrupt PPI in the stress response pathway comprising a transcription factor, Nrf2 that binds with another protein KEAP1. The beneficial effects of the Nrf2-KEAP1 pathway are well documented in different areas, including for neuroprotection and immune homeostasis. However, over-activation of the Nrf2 pathway can be deleterious owing to the activation tumor growth. The approach used by researchers to counter the over-activation of this pathway is to disrupt the PPI between Nrf2 and KEAP1 by non-covalent inhibitors. Different non-covalent small molecule inhibitors with varying degrees of potency and efficacy are in the stage of development and show activity comparable to covalent inhibitors.

Recognizing the role of PPIs as novel, promising drug targets, the Protein-Protein Interactions meeting at the DDC conference discussed key strategies and techniques for drug discovery. It went a long way in underlining the significance of this aspect of drug discovery by demonstrating the successes different researchers achieved in this endeavor.

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