5J4Y

The crystal structure of N-(4-(2-(thiazolo[5,4-c]pyridin-2-yl)phenoxy)phenyl)acetamide bound to JCV Helicase

Summary for 5J4Y

• Entry DOI: 10.2210/pdb5j4y/pdb
• Related: 5J40 5J47 5J4V
• Descriptor: Large T antigen, ZINC ION, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, ... (6 entities in total)
• Functional Keywords: helicase, hexamer, zn, atp, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: JC polyomavirus (JCPyV)
• Cellular location: Host nucleus : P03072
• Total number of polymer chains: 1
• Total formula weight: 43203.17

Authors

Ter Haar, E. (deposition date: 2016-04-01, release date: 2016-07-20, Last modification date: 2024-03-06)

Primary citation

Bonafoux, D.,Nanthakumar, S.,Bandarage, U.K.,Memmott, C.,Lowe, D.,Aronov, A.M.,Bhisetti, G.R.,Bonanno, K.C.,Coll, J.,Leeman, J.,Lepre, C.A.,Lu, F.,Perola, E.,Rijnbrand, R.,Taylor, W.P.,Wilson, D.,Zhou, Y.,Zwahlen, J.,Ter Haar, E.
Fragment-Based Discovery of Dual JC Virus and BK Virus Helicase Inhibitors.
J.Med.Chem., 59:7138-7151, 2016

PubMed 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.

PubMed: 27385654
DOI: 10.1021/acs.jmedchem.6b00486

Experimental method

X-RAY DIFFRACTION (2.59 Å)