title: Fragment-Based Discovery of Dual JC Virus and BK Virus Helicase Inhibitors.
abstract: There are currently no treatments for life-threatening infections caused by human polyomaviruses JCV and BKV. We therefore report herein the first crystal structure of the hexameric helicase of JCV large T antigen (apo) and its use to drive the structure-based design of dual JCV and BKV ATP-competitive inhibitors. The crystal structures obtained by soaking our early inhibitors into the JCV helicase allowed us to rapidly improve the biochemical activity of our inhibitors from 18 μM for the early 6-(2-methoxyphenyl)- and the 6-(2-ethoxyphenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole hits 1a and 1b to 0.6 μM for triazolopyridine 12i. In addition, we were able to demonstrate measurable antiviral activity in Vero cells for our thiazolopyridine series in the absence of marked cytotoxicity, thus confirming the usefulness of this approach.
authors.affiliation: Vertex Pharmaceuticals, Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Dominique
authors.initials: D
authors.lastname: Bonafoux
authors.affiliation: Vertex Pharmaceuticals, Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Suganthini
authors.initials: S
authors.lastname: Nanthakumar
authors.affiliation: Vertex Pharmaceuticals, Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Upul K
authors.initials: UK
authors.lastname: Bandarage
authors.affiliation: Vertex Pharmaceuticals, Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Christine
authors.initials: C
authors.lastname: Memmott
authors.affiliation: Vertex Pharmaceuticals, Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Derek
authors.initials: D
authors.lastname: Lowe
authors.affiliation: Vertex Pharmaceuticals, Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Alex M
authors.initials: AM
authors.lastname: Aronov
authors.affiliation: Vertex Pharmaceuticals, Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Govinda Rao
authors.initials: GR
authors.lastname: Bhisetti
authors.affiliation: Vertex Pharmaceuticals, Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Bonanno
authors.affiliation: Vertex Pharmaceuticals, Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Joyce
authors.initials: J
authors.lastname: Coll
authors.affiliation: Vertex Pharmaceuticals, Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Joshua
authors.initials: J
authors.lastname: Leeman
authors.affiliation: Vertex Pharmaceuticals, Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Lepre
authors.affiliation: Vertex Pharmaceuticals, Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Fan
authors.initials: F
authors.lastname: Lu
authors.affiliation: Vertex Pharmaceuticals, Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Perola
authors.affiliation: Vertex Pharmaceuticals, Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Rene
authors.initials: R
authors.lastname: Rijnbrand
authors.affiliation: Vertex Pharmaceuticals, Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: William P
authors.initials: WP
authors.lastname: Taylor
authors.affiliation: Vertex Pharmaceuticals, Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Dean
authors.initials: D
authors.lastname: Wilson
authors.affiliation: Vertex Pharmaceuticals, Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Vertex Pharmaceuticals, Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Jacque
authors.initials: J
authors.lastname: Zwahlen
authors.affiliation: Vertex Pharmaceuticals, Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Ernst
authors.initials: E
authors.lastname: Ter Haar
mesh_terms: D001739:BK Virus / Q000201:enzymology*; D004265:DNA Helicases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007577:JC Virus / Q000201:enzymology*; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D004265:DNA Helicases