title: Total synthesis and structure-activity relationship studies of a series of selective G protein inhibitors.
abstract: G proteins are key mediators of G protein-coupled receptor signalling, which facilitates a plethora of important physiological processes. The cyclic depsipeptides YM-254890 and FR900359 are the only known specific inhibitors of the Gqsubfamily of G proteins; however, no synthetic route has been reported previously for these complex natural products and they are not easily isolated from natural sources. Here we report the first total synthesis of YM-254890 and FR900359, as well as of two known analogues, YM-385780 and YM-385781. The versatility of the synthetic approach also enabled the design and synthesis of ten analogues, which provided the first structure-activity relationship study for this class of compounds. Pharmacological characterization of all the compounds at Gq-, Gi- and Gs-mediated signalling provided succinct information on the structural requirements for inhibition, and demonstrated that both YM-254890 and FR900359 are highly potent inhibitors of Gqsignalling, with FR900359 being the most potent. These natural products and their analogues represent unique tools for explorative studies of G protein inhibition.
authors: Department of Drug Design and Pharmacology, University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors: Xiao-Feng
authors: XF
authors: Xiong
authors: Department of Drug Design and Pharmacology, University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors: Hang
authors: H
authors: Zhang
authors: Department of Drug Design and Pharmacology, University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors: Christina R
authors: CR
authors: Underwood
authors: Department of Drug Design and Pharmacology, University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors: Kasper
authors: 0000-0002-9326-9644
authors: K
authors: Harpsøe
authors: Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
authors: Thomas J
authors: TJ
authors: Gardella
authors: Department of Drug Design and Pharmacology, University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors: Mie F
authors: MF
authors: Wöldike
authors: Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
authors: Michael
authors: M
authors: Mannstadt
authors: Department of Drug Design and Pharmacology, University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors: David E
authors: 0000-0002-4299-7561
authors: DE
authors: Gloriam
authors: Department of Drug Design and Pharmacology, University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors: Hans
authors: 0000-0001-9495-7388
authors: H
authors: Bräuner-Osborne
authors: Department of Drug Design and Pharmacology, University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors: Kristian
authors: 0000-0003-2206-4737
authors: K
authors: Strømgaard
mesh_terms: D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D047630:Depsipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D016296:Mutagenesis; D010456:Peptides, Cyclic / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D047630:Depsipeptides; D004791:Enzyme Inhibitors; C000607068:FR900359; D010456:Peptides, Cyclic; D043562:Receptors, G-Protein-Coupled; C475455:YM-254890; D043802:GTP-Binding Protein alpha Subunits, Gq-G11