The objective of this Core is to provide computational, bioinformatics and high throughput screening support for all three Projects. Computational support will include continued computer-aided design of new and/or improved inhibitors against SARS-CoV SCLpro and QSAR analysis of SCLpro inhibitor structures and activities to provide guidance in synthetic design (Project 3). Bioinformatics development of theoretical models for the 3-D structure of PLpro will be used as an initial foundation for PLpro structure-function studies (Project 1), for enzymatic mechanistic studies (Project 2) and for in silico screening of large chemical libraries for potential lead compounds (Projects). High throughput experimental screening will be used for initial lead discovery of PLpro inhibitors for Project 3; high throughput assays will be used for analysis of enzymatic mechanisms in Project 2. Bioinformatic analysis and modeling of protein substrate and protein-inhibitor interactions will be used to suggest particular mutations for hypothesis testing for enzymatic activity and mechanisms (Projects 1 and 2), and to predict inhibitor designs that will be least subject to mutational 'evasion'. This Core will thus provide centralized computational and high throughput assay screening for all three Projects.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI060915-03
Application #
7413696
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
3
Fiscal Year
2007
Total Cost
$342,837
Indirect Cost
Name
University of Illinois at Chicago
Department
Type
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Ghosh, Arun K; Reddy, Bhavanam Sekhara; Yen, Yu-Chen et al. (2016) Design of Potent and Highly Selective Inhibitors for Human ?-Secretase 2 (Memapsin 1), a Target for Type 2 Diabetes. Chem Sci 7:3117-3122
Báez-Santos, Yahira M; St John, Sarah E; Mesecar, Andrew D (2015) The SARS-coronavirus papain-like protease: structure, function and inhibition by designed antiviral compounds. Antiviral Res 115:21-38
Ratia, Kiira; Kilianski, Andrew; Baez-Santos, Yahira M et al. (2014) Structural Basis for the Ubiquitin-Linkage Specificity and deISGylating activity of SARS-CoV papain-like protease. PLoS Pathog 10:e1004113
Lee, Hyun; Mittal, Anuradha; Patel, Kavankumar et al. (2014) Identification of novel drug scaffolds for inhibition of SARS-CoV 3-Chymotrypsin-like protease using virtual and high-throughput screenings. Bioorg Med Chem 22:167-77
Jacobs, Jon; Grum-Tokars, Valerie; Zhou, Ya et al. (2013) Discovery, synthesis, and structure-based optimization of a series of N-(tert-butyl)-2-(N-arylamido)-2-(pyridin-3-yl) acetamides (ML188) as potent noncovalent small molecule inhibitors of the severe acute respiratory syndrome coronavirus (SARS-CoV) 3CL pr J Med Chem 56:534-46
Turlington, Mark; Chun, Aspen; Tomar, Sakshi et al. (2013) Discovery of N-(benzo[1,2,3]triazol-1-yl)-N-(benzyl)acetamido)phenyl) carboxamides as severe acute respiratory syndrome coronavirus (SARS-CoV) 3CLpro inhibitors: identification of ML300 and noncovalent nanomolar inhibitors with an induced-fit binding. Bioorg Med Chem Lett 23:6172-7
Lee, Hyun; Torres, Jaime; Truong, Lena et al. (2012) Reducing agents affect inhibitory activities of compounds: results from multiple drug targets. Anal Biochem 423:46-53
Sun, Li; Xing, Yaling; Chen, Xiaojuan et al. (2012) Coronavirus papain-like proteases negatively regulate antiviral innate immune response through disruption of STING-mediated signaling. PLoS One 7:e30802
Chaudhuri, Rima; Tang, Sishi; Zhao, Guijun et al. (2011) Comparison of SARS and NL63 papain-like protease binding sites and binding site dynamics: inhibitor design implications. J Mol Biol 414:272-88
Züst, Roland; Cervantes-Barragan, Luisa; Habjan, Matthias et al. (2011) Ribose 2'-O-methylation provides a molecular signature for the distinction of self and non-self mRNA dependent on the RNA sensor Mda5. Nat Immunol 12:137-43

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