PMID- 37322008
OWN - NLM
STAT- MEDLINE
DCOM- 20230619
LR  - 20231117
IS  - 2041-1723 (Electronic)
IS  - 2041-1723 (Linking)
VI  - 14
IP  - 1
DP  - 2023 Jun 15
TI  - N-Acryloylindole-alkyne (NAIA) enables imaging and profiling new ligandable 
      cysteines and oxidized thiols by chemoproteomics.
PG  - 3564
LID - 10.1038/s41467-023-39268-w [doi]
LID - 3564
AB  - Cysteine has been exploited as the binding site of covalent drugs. Its high 
      sensitivity to oxidation is also important for regulating cellular processes. To 
      identify new ligandable cysteines which can be hotspots for therapy and to better 
      study cysteine oxidations, we develop cysteine-reactive probes, 
      N-acryloylindole-alkynes (NAIAs), which have superior cysteine reactivity owing 
      to delocalization of pi electrons of the acrylamide warhead over the whole indole 
      scaffold. This allows NAIAs to probe functional cysteines more effectively than 
      conventional iodoacetamide-alkyne, and to image oxidized thiols by confocal 
      fluorescence microscopy. In mass spectrometry experiments, NAIAs successfully 
      capture new oxidized cysteines, as well as a new pool of ligandable cysteines and 
      proteins. Competitive activity-based protein profiling experiments further 
      demonstrate the ability of NAIA to discover lead compounds targeting these 
      cysteines and proteins. We show the development of NAIAs with activated 
      acrylamide for advancing proteome-wide profiling and imaging ligandable cysteines 
      and oxidized thiols.
CI  - (c) 2023. The Author(s).
FAU - Koo, Tin-Yan
AU  - Koo TY
AD  - School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of 
      Hong Kong, Hong Kong, P. R. China.
FAU - Lai, Hinyuk
AU  - Lai H
AD  - School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of 
      Hong Kong, Hong Kong, P. R. China.
FAU - Nomura, Daniel K
AU  - Nomura DK
AUID- ORCID: 0000-0003-1614-8360
AD  - Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA.
AD  - Department of Molecular and Cell Biology, University of California, Berkeley, 
      Berkeley, CA, USA.
FAU - Chung, Clive Yik-Sham
AU  - Chung CY
AUID- ORCID: 0000-0003-1382-719X
AD  - School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of 
      Hong Kong, Hong Kong, P. R. China. cyschung@hku.hk.
AD  - Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of 
      Medicine, The University of Hong Kong, Hong Kong, P. R. China. cyschung@hku.hk.
AD  - Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong, P. R. 
      China. cyschung@hku.hk.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230615
PL  - England
TA  - Nat Commun
JT  - Nature communications
JID - 101528555
RN  - K848JZ4886 (Cysteine)
RN  - 0 (Sulfhydryl Compounds)
RN  - 0 (Alkynes)
RN  - 0 (Proteins)
RN  - 0 (Acrylamides)
SB  - IM
MH  - *Cysteine/metabolism
MH  - *Sulfhydryl Compounds/chemistry
MH  - Alkynes/chemistry
MH  - Proteins/chemistry
MH  - Acrylamides
PMC - PMC10272157
COIS- A patent application from C.Y.-S.C., H.L., and T.-Y.K. has been filed for NAIA, 
      and the US patent application number is 18/307,905. D.K.N. is a co-founder, 
      shareholder, and scientific advisory board member for Frontier Medicines and 
      Vicinitas Therapeutics. D.K.N. is a member of the board of directors for 
      Vicinitas Therapeutics. D.K.N. is on the scientific advisory board of The Mark 
      Foundation for Cancer Research, MD Anderson Cancer Center, Photys Therapeutics, 
      Apertor Pharmaceuticals, Oerth Bio, and Chordia Therapeutics. D.K.N. is also an 
      Investment Advisory Board Member for Droia Ventures and a16z.
EDAT- 2023/06/16 01:08
MHDA- 2023/06/19 13:08
PMCR- 2023/06/15
CRDT- 2023/06/15 23:15
PHST- 2022/10/30 00:00 [received]
PHST- 2023/06/02 00:00 [accepted]
PHST- 2023/06/19 13:08 [medline]
PHST- 2023/06/16 01:08 [pubmed]
PHST- 2023/06/15 23:15 [entrez]
PHST- 2023/06/15 00:00 [pmc-release]
AID - 10.1038/s41467-023-39268-w [pii]
AID - 39268 [pii]
AID - 10.1038/s41467-023-39268-w [doi]
PST - epublish
SO  - Nat Commun. 2023 Jun 15;14(1):3564. doi: 10.1038/s41467-023-39268-w.