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SUMMARY:Mapping protein-protein interaction surfaces by photoactivable mol
 ecular fragments
DTSTART:20241121T161500
DTEND:20241121T171500
DTSTAMP:20260508T010605Z
UID:8fee2e7ae854bfa053ae68eb26f8fa03138853ba8d7b79a44f8c214c
CATEGORIES:Conferences - Seminars
DESCRIPTION:Prof. György M. Keserű\nProtein-protein interactions (PPIs) 
 represent viable therapeutic targets against diseases under transcriptiona
 l\, translational and signal transduction control. PPIs\, however\, are st
 ill considered as challenging targets for small molecules due to their ext
 ended and dynamic interacting surfaces providing only shallow trenches and
  grooves with distant binding hot spots. We introduced a new screening con
 cept that combines evolutionary optimized fragment pharmacophores with the
  use of a photoaffinity handle that enables high hit rates by LC-MS-based 
 detection. We have designed\, synthesized\, and screened 100 diazirine-tag
 ged small molecule fragments against protein-protein interactions represen
 ted by the oncogenic KRasG12D protein\, and the yet unliganded N-terminal 
 domain of the STAT5B transcription factor. We have discovered several new 
 fragment hits against all these targets and identified their binding sites
  via enzymatic digestion\, structural studies and modelling. These results
  revealed that the protocol outperforms screening traditional PPI targeted
  libraries in better exploration of the available binding sites and higher
  hit rates observed for even difficult targets.\nOur approach was recently
  extended to the development of proteomimetics screening a 100-membered ph
 otoreactive foldamer peptide fragment library. The members of this library
  act as local surface mimetics and identified functionally relevant protei
 n interfaces\, allosteric and previously unexplored targetable regions on 
 the surface of both PPI targets. Target-templated dynamic fragment linking
  of foldamer hits resulted in two orders of magnitude affinity improvement
  in a single step. The dimeric K-Ras ligand mimicked protein-like catalyti
 c functions. The photo-foldamer approach thus enables the highly efficient
  mapping of protein-protein interaction sites and provides a viable starti
 ng point for proteomimetic ligand development without a priori structural 
 hypotheses.
LOCATION:BCH 2218 https://plan.epfl.ch/?room=%3DBCH%202218&dim_floor=2&lan
 g=en&dim_lang=en&tree_groups=centres_nevralgiques_grp%2Cmobilite_acces_grp
 %2Crestauration_et_commerces_grp%2Censeignement%2Cservices_campus_grp%
STATUS:CONFIRMED
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