RT Journal Article
SR Electronic
T1 Designed PKC-targeting bryostatin analogs modulate innate immunity and neuroinflammation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.09.12.294918
DO 10.1101/2020.09.12.294918
A1 Efrat Abramson
A1 Clayton Hardman
A1 Akira Shimizu
A1 Soonmyung Hwang
A1 Lynda D. Hester
A1 Solomon H. Snyder
A1 Paul A. Wender
A1 Paul M. Kim
A1 Michael D. Kornberg
YR 2020
UL http://biorxiv.org/content/early/2020/09/12/2020.09.12.294918.abstract
AB Neuroinflammation characterizes multiple neurologic diseases, including primary inflammatory conditions such as multiple sclerosis (MS) and classical neurodegenerative diseases. Aberrant activation of the innate immune system contributes to disease progression in these conditions, but drugs that modulate innate immunity, particularly within the central nervous system (CNS), are lacking. The CNS-pene-trant natural product bryostatin-1 (bryo-1) attenuates neuroinflammation by targeting innate myeloid cells. Supplies of natural bryo-1 are limited but a recent scalable synthesis has enabled access to it and its analogs (termed bryologs), the latter providing a path to more efficacious, better tolerated, and more accessible agents. Here, we show that multiple synthetically accessible bryologs replicate the anti-inflammatory effects of bryo-1 on innate immune cells in vitro, and a lead bryolog attenuates neuroinflammation in vivo – actions mechanistically dependent on PKC binding. Our findings identify bryologs as promising drug candidates for targeting innate immunity in neuroinflammation and create a platform for evaluation of synthetic PKC modulators in neuroinflammatory diseases such as MS.Competing Interest StatementJohns Hopkins University and Stanford University have filed patent applications on this and related technology. Stanford University patent applications have been licensed by Neurotrope BioScience for the treatment of neurological disorders and by Bryologyx Inc. for use in HIV/AIDS eradication and cancer immunotherapy. P.A.W. is an advisor to both companies and a cofounder of the latter. M.D.K. has received consulting fees from OptumRx and Biogen Idec. The remaining authors declare no competing interests.