TY - JOUR
T1 - Discovery of a novel SHIP1 agonist that promotes degradation of lipid-laden phagocytic cargo by microglia
AU - Pedicone, Chiara
AU - Fernandes, Sandra
AU - Matera, Alessandro
AU - Meyer, Shea T.
AU - Loh, Stewart
AU - Ha, Jeung Hoi
AU - Bernard, Denzil
AU - Chisholm, John D.
AU - Paolicelli, Rosa Chiara
AU - Kerr, William G.
N1 - Funding Information:
This work was supported by NIH grant RO1 AG059717(to WGK and JDC), an ERC Starting Grant (REMIND 804949) (to RCP) and the Synapsis Foundation - Alzheimer Research Switzerland ARS (to RCP). W.G.K, C.P, A.M. and R.C.P. interpreted the data and wrote the manuscript with inputs from S.F. D.B. ran the computational screening. J.C. and S.M. designed the K306 synthesis, calculated K306 solubility, and provided K306 along with Atomwise for the studies. S.L. and J.H.H. provided the new cloning vector and contributed with molecular cloning skills with S.F. and C.P. for vector design. S.F. was responsible for the protein production. S.F. and C.P tested the agonists with in silico screening. C.P. performed in vitro IL-6 and TNF-α studies for BMDM and BV2 cells. A.M. and C.P. performed respectively confocal and flow cytometry assays for cargo uptake and degradation, PI(3,4)P2 studies and SHIP expression studies on gene-edited cells. Gene-edited cells were generated by A.M. and R.C.P. S.F. ran the iNOS study with a spectral analyzer. C.P. and S.F. performed in vivo studies for LPS endotoxemia. All the author edited and approved the final version of the paper, D.B. is an Atomwise employee. The other authors declare no competing interests.
Funding Information:
This work was supported by NIH grant RO1 AG059717 (to WGK and JDC), an ERC Starting Grant ( REMIND 804949 ) (to RCP) and the Synapsis Foundation - Alzheimer Research Switzerland ARS (to RCP).
Publisher Copyright:
© 2022 The Author(s)
PY - 2022/4/15
Y1 - 2022/4/15
N2 - Here, we describe the use of artificial intelligence to identify novel agonists of the SH2-containing 5′ inositol phosphatase 1 (SHIP1). One of the compounds, K306, represents the most potent agonist identified to date. We find that K306 exhibits selectivity for SHIP1 vs. the paralog enzyme SHIP2, and this activation does not require the C2 domain of SHIP1 which other known SHIP1 agonists require. Thus, K306 represents a new class of SHIP1 agonists with a novel mode of agonism. Importantly, we find that K306 can suppress induction of inflammatory cytokines and iNOS in macrophages or microglia, but not by their SHIP1-deficient counterparts. K306 also reduces TNF-α production in vivo in an LPS-induced endotoxemia assay. Finally, we show that K306 enhances phagolysosomal degradation of synaptosomes and dead neurons by microglia revealing a novel function for SHIP1 that might be exploited therapeutically in dementia.
AB - Here, we describe the use of artificial intelligence to identify novel agonists of the SH2-containing 5′ inositol phosphatase 1 (SHIP1). One of the compounds, K306, represents the most potent agonist identified to date. We find that K306 exhibits selectivity for SHIP1 vs. the paralog enzyme SHIP2, and this activation does not require the C2 domain of SHIP1 which other known SHIP1 agonists require. Thus, K306 represents a new class of SHIP1 agonists with a novel mode of agonism. Importantly, we find that K306 can suppress induction of inflammatory cytokines and iNOS in macrophages or microglia, but not by their SHIP1-deficient counterparts. K306 also reduces TNF-α production in vivo in an LPS-induced endotoxemia assay. Finally, we show that K306 enhances phagolysosomal degradation of synaptosomes and dead neurons by microglia revealing a novel function for SHIP1 that might be exploited therapeutically in dementia.
KW - Artificial intelligence
KW - Biochemical mechanism
KW - Biochemistry
KW - Cellular neuroscience
KW - Health sciences
UR - http://www.scopus.com/inward/record.url?scp=85127821431&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85127821431&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2022.104170
DO - 10.1016/j.isci.2022.104170
M3 - Article
AN - SCOPUS:85127821431
SN - 2589-0042
VL - 25
JO - iScience
JF - iScience
IS - 4
M1 - 104170
ER -