Optimized M24B aminopeptidase inhibitors for CARD8 inflammasome activation Journal Article

   


Authors: Chen, Q.; Wang, A.; Covelli, D. J.; Bhattacharjee, A.; Wang, Q.; Orth-He, E. L.; Rao, S. D.; Huang, H. C.; Ball, D. P.; Hsiao, J. C.; Bachovchin, D. A.
Article Title: Optimized M24B aminopeptidase inhibitors for CARD8 inflammasome activation
Abstract: Inflammasomes are innate immune signaling platforms that trigger pyroptotic cell death. NLRP1 and CARD8 are related human inflammasomes that detect similar danger signals, but NLRP1 has a higher activation threshold and triggers a more inflammatory form of pyroptosis. Both sense the accumulation of intracellular peptides with Xaa-Pro N-termini, but Xaa-Pro peptides on their own without a second danger signal only activate the CARD8 inflammasome. We recently reported that a dual inhibitor of the Xaa-Pro-cleaving M24B aminopeptidases PEPD and XPNPEP1 called CQ31 selectively activates the CARD8 inflammasome by inducing the build-up of Xaa-Pro peptides. Here, we performed structure-activity relationship studies on CQ31 to develop the optimized dual PEPD/XPNPEP1 inhibitor CQ80 that more effectively induces CARD8 inflammasome activation. We anticipate that CQ80 will become a valuable tool to study the basic biology and therapeutic potential of selective CARD8 inflammasome activation. © 2023 American Chemical Society.
Keywords: signal transduction; metabolism; neoplasm proteins; apoptosis regulatory proteins; tumor protein; apoptosis regulatory protein; caspase recruitment domain signaling protein; aminopeptidase; pyroptosis; inflammasome; card signaling adaptor proteins; inflammasomes; humans; human; aminopeptidases; card8 protein, human
Journal Title: Journal of Medicinal Chemistry
Volume: 66
Issue: 4
ISSN: 0022-2623
Publisher: American Chemical Society  
Date Published: 2023-02-23
Start Page: 2589
End Page: 2607
Language: English
DOI: 10.1021/acs.jmedchem.2c01535
PUBMED: 36724486
PROVIDER: scopus
PMCID: PMC10149104
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85147513896&doi=10.1021%2facs.jmedchem.2c01535&partnerID=40&md5=fc1b96730a7f6d425dcf64c7ccc0a086
Notes: Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Daniel Bachovchin -- Source: Scopus
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MSK Authors
  1. Daniel Bachovchin
    35 Bachovchin
  2. Sahana Dinesh Rao
    13 Rao
  3. Daniel Parker Ball
    14 Ball
  4. Elizabeth Lucille Orth
    10 Orth
  5. Abir Bhattacharjee
    5 Bhattacharjee
  6. Hsin-Che Huang
    12 Huang
  7. Qinghui Wang
    8 Wang
  8. Chieh Hsiao
    6 Hsiao
  9. Qifeng Chen
    3 Chen
  10. Dominic Covelli
    2 Covelli
  11. Alvin Wang
    2 Wang
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