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SUMMARY:Towards Covalent Inhibitors Addressing Diverse Amino Acids – Unb
 iased Profiling of the Proteome-Wide Selectivity of Electrophiles
DTSTART:20221018T111500
DTEND:20221018T121500
DTSTAMP:20260916T054421Z
UID:b43dd982d4b88a8b72ff9f86ed404600ae255444728190da304a5805
CATEGORIES:Conferences - Seminars
DESCRIPTION:Prof. Stephan Hacker (Leiden University)\nThe potency and sele
 ctivity offered by covalent inhibitors have led to a resurgence of their a
 pplication in drug discovery.1 In this context\, modern residue-specific c
 hemoproteomic approaches allow the highly parallel profiling of the ligand
 ability of whole proteomes with resolution of the targeted amino acid. 2\,
 3\,4 This enables the simultaneous identification of many new ligandable b
 inding sites in potential target proteins for therapeutic intervention alo
 ngside first ligands to interrogate their function.\n\nOur group is develo
 ping covalent inhibitors in the context of antibiotics\, because new drugg
 able antibacterial targets are urgently needed to overcome bacterial resis
 tance.5 We have developed a tailored method for residue-specific chemoprot
 eomics in bacteria that we term isoDTB-ABPP (Figure 1).2 We have applied 
 this technology for the screening of cysteine-directed ligands in S. aure
 us and identified >250 binding sites that can be addressed with covalent l
 igands and that are starting points for the development of novel antibioti
 cs.\n\nFurthermore\, we are developing new chemotypes to globally investig
 ate a variety of other amino acids. Here\, we have recently profiled more 
 than 50 electrophilic alkyne probes for their proteome-wide reactivity and
  selectivity6 and identified first‑in‑class probes to globally study a
 spartates and glutamates7 as well as arginines\, histidines and tryptophan
 s in the proteome.6 These studies will help us to identify a plethora of n
 ew druggable bacterial targets that can be addressed with novel antibiotic
 s.\n\n\n\nReferences:\n1.         J. Singh et al. (2011) Nat. Rev.
  Drug. Discov. 10\, 307-317.\n2.         P. R. A. Zanon et al. (20
 20) Angew. Chem. Int. Ed. 59\, 2829-2836.\n3.         K. M. Backus
  et al. (2016) Nature 534\, 570-574\n4.         S. M. Hacker et al
 . (2017) Nature Chem. 9\, 1181-1190.\n5.         M. Lakemeyer et a
 l. (2018) Angew. Chem. Int. Ed. 57\, 14440-14475.\n6.         P. R
 . A. Zanon et al. (2021) ChemRxiv\, doi: 10.33774/chemrxiv-2021-w7rss-v2\n
 7.         K. Bach et al. (2020) ACS Cent. Sci. 6\, 546-554.\n 
LOCATION:CH G1 495 https://plan.epfl.ch/?room==CH%20G1%20495
STATUS:CONFIRMED
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