Structure-guided design and optimization of dipeptidyl inhibitors of norovirus 3CL protease. Structure-activity relationships and biochemical, X-ray crystallographic, cell-based, and in vivo studies

Anushka C. Galasiti Kankanamalage; Yunjeong Kim; Pathum M. Weerawarna; Roxanne Adeline Z. Uy; Vishnu C. Damalanka; Sivakoteswara Rao Mandadapu; Kevin R. Alliston; Nurjahan Mehzabeen; Kevin P. Battaile; Scott Lovell; Kyeong Ok Chang; William C. Groutas

doi:10.1021/jm5019934

Structure-guided design and optimization of dipeptidyl inhibitors of norovirus 3CL protease. Structure-activity relationships and biochemical, X-ray crystallographic, cell-based, and in vivo studies

Anushka C. Galasiti Kankanamalage, Yunjeong Kim, Pathum M. Weerawarna, Roxanne Adeline Z. Uy, Vishnu C. Damalanka, Sivakoteswara Rao Mandadapu, Kevin R. Alliston, Nurjahan Mehzabeen, Kevin P. Battaile, Scott Lovell, Kyeong Ok Chang, William C. Groutas

Department of Biochemistry & Molecular Biophysics

Research output: Contribution to journal › Article › peer-review

47 Scopus citations

Abstract

Norovirus infection constitutes the primary cause of acute viral gastroenteritis. There are currently no vaccines or norovirus-specific antiviral therapeutics available for the management of norovirus infection. Norovirus 3C-like protease is essential for viral replication, consequently, inhibition of this enzyme is a fruitful avenue of investigation that may lead to the emergence of antinorovirus therapeutics. We describe herein the optimization of dipeptidyl inhibitors of norovirus 3C-like protease using iterative SAR, X-ray crystallographic, and enzyme and cell-based studies. We also demonstrate herein in vivo efficacy of an inhibitor using the murine model of norovirus infection.

Original language	English
Pages (from-to)	3144-3155
Number of pages	12
Journal	Journal of Medicinal Chemistry
Volume	58
Issue number	7
DOIs	https://doi.org/10.1021/jm5019934
State	Published - Apr 9 2015

Access to Document

10.1021/jm5019934

Cite this

Galasiti Kankanamalage, A. C., Kim, Y., Weerawarna, P. M., Uy, R. A. Z., Damalanka, V. C., Mandadapu, S. R., Alliston, K. R., Mehzabeen, N., Battaile, K. P., Lovell, S., Chang, K. O., & Groutas, W. C. (2015). Structure-guided design and optimization of dipeptidyl inhibitors of norovirus 3CL protease. Structure-activity relationships and biochemical, X-ray crystallographic, cell-based, and in vivo studies. Journal of Medicinal Chemistry, 58(7), 3144-3155. https://doi.org/10.1021/jm5019934

@article{63dbab0b573c485f976711a237241b4b,

title = "Structure-guided design and optimization of dipeptidyl inhibitors of norovirus 3CL protease. Structure-activity relationships and biochemical, X-ray crystallographic, cell-based, and in vivo studies",

abstract = "Norovirus infection constitutes the primary cause of acute viral gastroenteritis. There are currently no vaccines or norovirus-specific antiviral therapeutics available for the management of norovirus infection. Norovirus 3C-like protease is essential for viral replication, consequently, inhibition of this enzyme is a fruitful avenue of investigation that may lead to the emergence of antinorovirus therapeutics. We describe herein the optimization of dipeptidyl inhibitors of norovirus 3C-like protease using iterative SAR, X-ray crystallographic, and enzyme and cell-based studies. We also demonstrate herein in vivo efficacy of an inhibitor using the murine model of norovirus infection.",

author = "{Galasiti Kankanamalage}, {Anushka C.} and Yunjeong Kim and Weerawarna, {Pathum M.} and Uy, {Roxanne Adeline Z.} and Damalanka, {Vishnu C.} and Mandadapu, {Sivakoteswara Rao} and Alliston, {Kevin R.} and Nurjahan Mehzabeen and Battaile, {Kevin P.} and Scott Lovell and Chang, {Kyeong Ok} and Groutas, {William C.}",

note = "Publisher Copyright: {\textcopyright} 2015 American Chemical Society.",

year = "2015",

month = apr,

day = "9",

doi = "10.1021/jm5019934",

language = "English",

volume = "58",

pages = "3144--3155",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

number = "7",

}

Galasiti Kankanamalage, AC, Kim, Y, Weerawarna, PM, Uy, RAZ, Damalanka, VC, Mandadapu, SR, Alliston, KR, Mehzabeen, N, Battaile, KP, Lovell, S, Chang, KO & Groutas, WC 2015, 'Structure-guided design and optimization of dipeptidyl inhibitors of norovirus 3CL protease. Structure-activity relationships and biochemical, X-ray crystallographic, cell-based, and in vivo studies', Journal of Medicinal Chemistry, vol. 58, no. 7, pp. 3144-3155. https://doi.org/10.1021/jm5019934

Structure-guided design and optimization of dipeptidyl inhibitors of norovirus 3CL protease. Structure-activity relationships and biochemical, X-ray crystallographic, cell-based, and in vivo studies. / Galasiti Kankanamalage, Anushka C.; Kim, Yunjeong; Weerawarna, Pathum M. et al.
In: Journal of Medicinal Chemistry, Vol. 58, No. 7, 09.04.2015, p. 3144-3155.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Structure-guided design and optimization of dipeptidyl inhibitors of norovirus 3CL protease. Structure-activity relationships and biochemical, X-ray crystallographic, cell-based, and in vivo studies

AU - Galasiti Kankanamalage, Anushka C.

AU - Kim, Yunjeong

AU - Weerawarna, Pathum M.

AU - Uy, Roxanne Adeline Z.

AU - Damalanka, Vishnu C.

AU - Mandadapu, Sivakoteswara Rao

AU - Alliston, Kevin R.

AU - Mehzabeen, Nurjahan

AU - Battaile, Kevin P.

AU - Lovell, Scott

AU - Chang, Kyeong Ok

AU - Groutas, William C.

PY - 2015/4/9

Y1 - 2015/4/9

N2 - Norovirus infection constitutes the primary cause of acute viral gastroenteritis. There are currently no vaccines or norovirus-specific antiviral therapeutics available for the management of norovirus infection. Norovirus 3C-like protease is essential for viral replication, consequently, inhibition of this enzyme is a fruitful avenue of investigation that may lead to the emergence of antinorovirus therapeutics. We describe herein the optimization of dipeptidyl inhibitors of norovirus 3C-like protease using iterative SAR, X-ray crystallographic, and enzyme and cell-based studies. We also demonstrate herein in vivo efficacy of an inhibitor using the murine model of norovirus infection.

AB - Norovirus infection constitutes the primary cause of acute viral gastroenteritis. There are currently no vaccines or norovirus-specific antiviral therapeutics available for the management of norovirus infection. Norovirus 3C-like protease is essential for viral replication, consequently, inhibition of this enzyme is a fruitful avenue of investigation that may lead to the emergence of antinorovirus therapeutics. We describe herein the optimization of dipeptidyl inhibitors of norovirus 3C-like protease using iterative SAR, X-ray crystallographic, and enzyme and cell-based studies. We also demonstrate herein in vivo efficacy of an inhibitor using the murine model of norovirus infection.

UR - http://www.scopus.com/inward/record.url?scp=84927759277&partnerID=8YFLogxK

U2 - 10.1021/jm5019934

DO - 10.1021/jm5019934

M3 - Article

C2 - 25761614

AN - SCOPUS:84927759277

SN - 0022-2623

VL - 58

SP - 3144

EP - 3155

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 7

ER -

Galasiti Kankanamalage AC, Kim Y, Weerawarna PM, Uy RAZ, Damalanka VC, Mandadapu SR et al. Structure-guided design and optimization of dipeptidyl inhibitors of norovirus 3CL protease. Structure-activity relationships and biochemical, X-ray crystallographic, cell-based, and in vivo studies. Journal of Medicinal Chemistry. 2015 Apr 9;58(7):3144-3155. doi: 10.1021/jm5019934

Structure-guided design and optimization of dipeptidyl inhibitors of norovirus 3CL protease. Structure-activity relationships and biochemical, X-ray crystallographic, cell-based, and in vivo studies

Abstract

Access to Document

Other files and links

Fingerprint

Cite this