James H. Frederich
Florida State University
Exploiting Natural Products for the Rational Design of Protein-Protein Interaction Stabilizers
The association of proteins into protein complexes is a dynamic process involved in the regulation and execution of virtually all biochemical processes. It is therefore not surprising that protein-protein interactions (PPIs) are implicated in the pathobiology most diseases. Accordingly, targeted manipulation of PPIs has emerged as a cutting-edge area of research at the chemistry-biology interface. Small-molecule-based approaches for PPI modulation focus on inhibiting PPIs, typically via peptidomimetics designed to replicate a conformational epitope involved in molecular recognition. However, in comparison, the complementary strategy of developing small-molecule PPI stabilizers remains underexplored in drug discovery.
Research in the Frederich Lab focuses on the chemistry and biology of natural products that function as PPI stabilizers. The objective of our program is to refine these scaffolds into selective chemical tools with optimized pharmacological profiles. This work is exemplified by fusicoccin A (FC-A), a structurally complex diterpene glycoside that targets 14-3-3 functions in vivo. Upon entering cells, FC-A binds to a select group of 14-3-3·client protein complexes and enhances the lifetime of these PPIs by forming simultaneous contacts with both proteins. This biology inspired the design of ISIR-05, a semi-synthetic analog of FC-A with peripheral structural modifications that alter binding affinity and selectivity for 14-3-3 PPIs in human cell culture. These observations led us to hypothesize that FC-A can scaffold a new class of 14-3-3 PPI stabilizers with enhanced specificity profiles; however, the structural complexity of highly oxidized diterpene limits practical entry to designed, fully-synthetic FC-A variants. To address this limitation, we have developed a modular total synthesis of the fusicoccin diterpene that is able to support deep-seeded structural investigations. This lecture will describe the evolution of strategies and tactics explored en route to fusicoccin, and our efforts to characterize the structural features of FC-A that impart selectivity for certain 14-3-3·client protein PPI interfaces in vitro.