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:Professor Jim FrederichFlorida State UniversityHosted by Professor Jeehiun Lee\nTuesday February 26, 2018\n11:00AM, CCB Auditorium\n“Exploiting Natura l Products for the Rational Design of Protein-Protein Interaction Stabalize rs”\nThe association of proteins into protein complexes is a dynamic proces s involved in the regulation and execution of virtually all biochemical pro cesses. It is therefore not surprising that protein-protein interactions (P PIs) are implicated in the pathobiology most diseases. Accordingly, targete d manipulation of PPIs has emerged as a cutting-edge area of research at th e chemistry-biology interface. Small-molecule-based approaches for PPI modu lation focus on inhibiting PPIs, typically via peptidomimetics designed to replicate a conformational epitope involved in molecular recognition. Howev er, in comparison, the complementary strategy of developing small-molecule PPI stabilizers remains underexplored in drug discovery.\nResearch in the F rederich Lab focuses on the chemistry and biology of natural products that function as PPI stabilizers. The objective of our program is to refine thes e scaffolds into selective chemical tools with optimized pharmacological pr ofiles. This work is exemplified by fusicoccin A (FC-A), a structurally com plex diterpene glycoside that targets 14-3-3 functions in vivo. Upon enteri ng cells, FC-A binds to a select group of 14-3-3·client protein complexes a nd enhances the lifetime of these PPIs by forming simultaneous contacts wit h both proteins. This biology inspired the design of ISIR-05, a semi-synthe tic analog of FC-A with peripheral structural modifications that alter bind ing affinity and selectivity for 14-3-3 PPIs in human cell culture. These o bservations led us to hypothesize that FC-A can scaffold a new class of 14- 3-3 PPI stabilizers with enhanced specificity profiles; however, the struct ural complexity of highly oxidized diterpene limits practical entry to desi gned, fully-synthetic FC-A variants. To address this limitation, we have de veloped a modular total synthesis of the fusicoccin diterpene that is able to support deep-seeded structural b investigations. This lecture will descr ibe the evolution of strategies and tactics explored en route to fusicoccin , and our efforts to characterize the structural features of FC-A that impa rt selectivity for certain 14-3-3·client protein PPI interfaces in vitro.\n ~Coffee/tea will be served prior to lecture.~\n X-ALT-DESC;FMTTYPE=text/html:
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:20240328T181016 DTSTART:20190226T160000 DTEND:20190226T170000 SEQUENCE:0 TRANSP:OPAQUE END:VEVENT END:VCALENDAR