Synthetic small molecule furin inhibitors derived from 2,5-dideoxystreptamine.
Furin plays a crucial role in embryogenesis and homeostasis and in diseases such as Alzheimer's disease, cancer, and viral and bacterial infections. Thus, inhibition of furin may provide a feasible and promising approach for therapeutic intervention of furin-mediated disease mechanisms. Here, we report on a class of small molecule furin inhibitors based on 2,5-dideoxystreptamine. Derivatization of 2,5-dideoxystreptamine by the addition of guanidinylated aryl groups yielded a set of furin inhibitors with nanomolar range potency against furin when assayed in a biochemical cleavage assay. Moreover, a subset of these furin inhibitors protected RAW 264.7 macrophage cells from toxicity caused by furin-dependent processing of anthrax protective antigen. These inhibitors were found to behave as competitive inhibitors of furin and to be relatively specific for furin. Molecular modeling revealed that these inhibitors may target the active site of furin as they showed site occupancy similar to the alkylating inhibitor decanoyl-Arg-Val-Lys-Arg-CH(2)Cl. The compounds presented here are bona fide synthetic small molecule furin inhibitors that exhibit potency in the nanomolar range, suggesting that they may serve as valuable tools for studying furin action and potential therapeutics agents for furin-dependent diseases.
Jiao
Guan-Sheng
GS
Departments of Chemistry, PanThera Biopharma LLC, 99-193 Aiea Heights Drive, Suite 136, Aiea, HI 96701, USA. gjiao@pantherabio.com
Cregar
Lynne
L
Wang
Jinzhi
J
Millis
Sherri Z
SZ
Tang
Cho
C
O'Malley
Sean
S
Johnson
Alan T
AT
Sareth
Sina
S
Larson
Jason
J
Thomas
Gary
G
D000818:Animals; D002460:Cell Line; D019295:Computational Biology; D045683:Furin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006595:Hexosamines / Q000737:chemistry*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
C516923:2,5-dideoxystreptamine; D006595:Hexosamines; D015842:Serine Proteinase Inhibitors; D045683:Furin