TY - JOUR
T1 - Structure-guided design, synthesis and evaluation of oxazolidinone-based inhibitors of norovirus 3CL protease
AU - Damalanka, Vishnu C.
AU - Kim, Yunjeong
AU - Galasiti Kankanamalage, Anushka C.
AU - Rathnayake, Athri D.
AU - Mehzabeen, Nurjahan
AU - Battaile, Kevin P.
AU - Lovell, Scott
AU - Nguyen, Harry Nhat
AU - Lushington, Gerald H.
AU - Chang, Kyeong Ok
AU - Groutas, William C.
N1 - Funding Information:
The generous financial support of this work by the National Institutes of Health ( AI109039 ) is gratefully acknowledged. Use of the University of Kansas Protein Structure Laboratory was supported by a grant from the National Institute of General Medical Sciences ( P30GM110761 ) of the National Institutes of Health. Use of the IMCA-CAT beamline 17-ID at the Advanced Photon Source was supported by the companies of the Industrial Macromolecular Crystallography Association through a contract with Hauptman-Woodward Medical Research Institute . Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under contract no. DE-AC02-06CH11357 .
Publisher Copyright:
© 2017 Elsevier Masson SAS
PY - 2018/1/1
Y1 - 2018/1/1
N2 - Acute nonbacterial gastroenteritis caused by noroviruses constitutes a global public health concern and a significant economic burden. There are currently no small molecule therapeutics or vaccines for the treatment of norovirus infections. A structure-guided approach was utilized in the design of a series of inhibitors of norovirus 3CL protease that embody an oxazolidinone ring as a novel design element for attaining optimal binding interactions. Low micromolar cell-permeable inhibitors that display anti-norovirus activity have been identified. The mechanism of action, mode of binding, and structural rearrangements associated with the interaction of the inhibitors and the enzyme were elucidated using X-ray crystallography.
AB - Acute nonbacterial gastroenteritis caused by noroviruses constitutes a global public health concern and a significant economic burden. There are currently no small molecule therapeutics or vaccines for the treatment of norovirus infections. A structure-guided approach was utilized in the design of a series of inhibitors of norovirus 3CL protease that embody an oxazolidinone ring as a novel design element for attaining optimal binding interactions. Low micromolar cell-permeable inhibitors that display anti-norovirus activity have been identified. The mechanism of action, mode of binding, and structural rearrangements associated with the interaction of the inhibitors and the enzyme were elucidated using X-ray crystallography.
UR - http://www.scopus.com/inward/record.url?scp=85037985634&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2017.12.014
DO - 10.1016/j.ejmech.2017.12.014
M3 - Article
C2 - 29227928
AN - SCOPUS:85037985634
VL - 143
SP - 881
EP - 890
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
ER -