title: Synthetic small molecule furin inhibitors derived from 2,5-dideoxystreptamine.
abstract: 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.
authors.affiliation: Departments of Chemistry, PanThera Biopharma LLC, 99-193 Aiea Heights Drive, Suite 136, Aiea, HI 96701, USA. gjiao@pantherabio.com
authors.forename: Guan-Sheng
authors.initials: GS
authors.lastname: Jiao
authors.forename: Lynne
authors.initials: L
authors.lastname: Cregar
authors.forename: Jinzhi
authors.initials: J
authors.lastname: Wang
authors.forename: Sherri Z
authors.initials: SZ
authors.lastname: Millis
authors.forename: Cho
authors.initials: C
authors.lastname: Tang
authors.forename: Sean
authors.initials: S
authors.lastname: O'Malley
authors.forename: Alan T
authors.initials: AT
authors.lastname: Johnson
authors.forename: Sina
authors.initials: S
authors.lastname: Sareth
authors.forename: Jason
authors.initials: J
authors.lastname: Larson
authors.forename: Gary
authors.initials: G
authors.lastname: Thomas
mesh_terms: 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
chemical_list: C516923:2,5-dideoxystreptamine; D006595:Hexosamines; D015842:Serine Proteinase Inhibitors; D045683:Furin