BEGIN:VCALENDAR VERSION:2.0 PRODID:-//jEvents 2.0 for Joomla//EN CALSCALE:GREGORIAN METHOD:PUBLISH BEGIN:VEVENT UID:12d9cbe8375a0622ace12cf604e19891 CATEGORIES:Colloquium CREATED:20181017T154802 SUMMARY:Professor Jim Frederich DESCRIPTION:
Hoste d by Professor Jeehiun Lee
Tuesday February 26, 2018
11:00AM, CCB Auditorium
“Exploiting Natural Products for the Rational Design of Protein -Protein Interaction Stabalizers”
The association of proteins into pr otein complexes is a dynamic process involved in the regulation and executi on of virtually all biochemical processes. It is therefore not surprising t hat protein-protein interactions (PPIs) are implicated in the pathobio logy most diseases. Accordingly, targeted manipulation of PPIs has emerged as a cutting-edge area of research at the chemistry-biology interface. Smal l-molecule-based approaches for PPI modulation focus on inhibiting PPIs, ty pically via peptidomimetics designed to replicate a conformational epitope involved in molecular recognition. However, in comparison, the complementar y strategy of developing small-molecule PPI stabilizers remains underexplor ed in drug discovery.
Research in the Frederich Lab focuses on the ch emistry and biology of natural products that function as PPI stabilizers. T he objective of our program is to refine these scaffolds into selective che mical tools with optimized pharmacological profiles. This work is exemplifi ed 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 life time of these PPIs by forming simultaneous contacts with both proteins. Thi s biology inspired the design of ISIR-05, a semi-synthetic analog of FC-A w ith peripheral structural modifications that alter binding affinity and sel ectivity for 14-3-3 PPIs in human cell culture. These observations led us t o hypothesize that FC-A can scaffold a new class of 14-3-3 PPI stabilizers with enhanced specificity profiles; however, the structural complexity of h ighly oxidized diterpene limits practical entry to designed, fully-syn thetic FC-A variants. To address this limitation, we have developed a modul ar total synthesis of the fusicoccin diterpene that is able to support deep -seeded structural b investigations. This lecture will describe the ev olution of strategies and tactics explored en route to fusicoccin, and our efforts to characterize the structural features of FC-A that impart selecti vity for certain 14-3-3·client protein PPI interfaces in vitro.
Hosted by Professor Jeehiun Lee
11:00AM, CCB Auditorium
“Exploiting Natural Products for the Rat ional Design of Protein-Protein Interaction Stabalizers”
The ass ociation of proteins into protein complexes is a dynamic process involved i n the regulation and execution of virtually all biochemical processes. It i s therefore not surprising that protein-protein interactions (PPIs) ar e implicated in the pathobiology most diseases. Accordingly, targeted manip ulation of PPIs has emerged as a cutting-edge area of research at the chemi stry-biology interface. Small-molecule-based approaches for PPI modulation focus on inhibiting PPIs, typically via peptidomimetics designed to replica te a conformational epitope involved in molecular recognition. However, in comparison, the complementary strategy of developing small-molecule PPI sta bilizers remains underexplored in drug discovery.
Research in the Fre derich Lab focuses on the chemistry and biology of natural products that fu nction as PPI stabilizers. The objective of our program is to refine these scaffolds into selective chemical tools with optimized pharmacological prof iles. This work is exemplified by fusicoccin A (FC-A), a structurally compl ex diterpene glycoside that targets 14-3-3 functions in vivo. Upon ent ering cells, FC-A binds to a select group of 14-3-3·client protein complexe s and enhances the lifetime of these PPIs by forming simultaneous cont acts with both proteins. This biology inspired the design of ISIR-05, a sem i-synthetic analog of FC-A with peripheral structural modifications that al ter 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 clas s of 14-3-3 PPI stabilizers with enhanced specificity profiles; however, th e structural complexity of highly oxidized diterpene limits practical entry to designed, fully-synthetic FC-A variants. To address this limitatio n, we have developed a modular total synthesis of the fusicoccin diterpene that is able to support deep-seeded structural b investigations. This lecture will describe the evolution of strategies and tactics explored en r oute to fusicoccin, and our efforts to characterize the structural features of FC-A that impart selectivity for certain 14-3-3·client protein PPI inte rfaces in vitro.
~Coffee/tea will be served prior to lecture. ~
DTSTAMP:20240329T065851 DTSTART:20190226T160000 DTEND:20190226T170000 SEQUENCE:0 TRANSP:OPAQUE END:VEVENT END:VCALENDAR