Transient Protein-Protein Interactions (PPIs) are central mediators of protein activity and signaling network and their modulation has significant impact on cell metabolism and regulation. They are therefore considered promising, albeit challenging, opportunities to expand druggable chemical space. However, due to the transient nature of these interactions, this class of PPIs is particularly challenging to characterize and drug. In addition to significant challenges with valid bioassay results, in the context of drug discovery, the lack of structural information hampers the rational design of PPI modulators.
Herein, we describe the development of a native mass spectrometry (MS) methodology to elucidate new and biologically relevant, interfacial characteristics of the transient HOP-HSP90 PPI, which though medicinal chemistry and chemical biology workflows, have translated into promising probe compounds for studying Kaposi’s sarcoma herpes associated virus (KSHV), the causative agent of the HIV related Kaposi’s sarcoma.
The lecture will conclude by discussing the development of Native MS capacity at the University of Cape Town and the application of native MS to contemporary modalities to drug discovery.
