TY - JOUR
T1 - Structure-based exploration and exploitation of the S4subsite of norovirus 3CL protease in the design of potent and permeable inhibitors
AU - Galasiti Kankanamalage, Anushka C.
AU - Kim, Yunjeong
AU - Rathnayake, Athri D.
AU - Damalanka, Vishnu C.
AU - Weerawarna, Pathum M.
AU - Doyle, Sean T.
AU - Alsoudi, Amer F.
AU - Dissanayake, D. M.Padmasankha
AU - Lushington, Gerald H.
AU - Mehzabeen, Nurjahan
AU - Battaile, Kevin P.
AU - Lovell, Scott
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 ) from 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:
© 2016
PY - 2017
Y1 - 2017
N2 - Human noroviruses are the primary cause of epidemic and sporadic acute gastroenteritis. The worldwide high morbidity and mortality associated with norovirus infections, particularly among the elderly, immunocompromised patients and children, constitute a serious public health concern. There are currently no approved human vaccines or norovirus-specific small-molecule therapeutics or prophylactics. Norovirus 3CL protease has recently emerged as a potential therapeutic target for the development of anti-norovirus agents. We hypothesized that the S4subsite of the enzyme may provide an effective means of designing potent and cell permeable inhibitors of the enzyme. We report herein the structure-guided exploration and exploitation of the S4subsite of norovirus 3CL protease in the design and synthesis of effective inhibitors of the protease.
AB - Human noroviruses are the primary cause of epidemic and sporadic acute gastroenteritis. The worldwide high morbidity and mortality associated with norovirus infections, particularly among the elderly, immunocompromised patients and children, constitute a serious public health concern. There are currently no approved human vaccines or norovirus-specific small-molecule therapeutics or prophylactics. Norovirus 3CL protease has recently emerged as a potential therapeutic target for the development of anti-norovirus agents. We hypothesized that the S4subsite of the enzyme may provide an effective means of designing potent and cell permeable inhibitors of the enzyme. We report herein the structure-guided exploration and exploitation of the S4subsite of norovirus 3CL protease in the design and synthesis of effective inhibitors of the protease.
KW - 3CL protease
KW - Norovirus
KW - Optimization
KW - S4 subsite
UR - http://www.scopus.com/inward/record.url?scp=85002125623&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2016.11.027
DO - 10.1016/j.ejmech.2016.11.027
M3 - Article
C2 - 27914364
AN - SCOPUS:85002125623
SN - 0223-5234
VL - 126
SP - 502
EP - 516
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
ER -