Noroviruses (NIAID category B priority pathogens) are a leading cause of food- or water-borne gastroenteritis outbreaks, responsible for an estimated 23 million cases annually in the US. However, currently there are no commercially available vaccines or antivirals against noroviruses. We have initiated a comprehensive plan aimed at developing anti-noroviral therapeutics in cooperation with medicinal chemists and virologists from various institutes. Using a novel cell-based Norwalk virus (NV) replication system, we have identified viral proteinase (Pro) and cellular acyl-coenzyme Axholesterol acyltransferase (ACAT) as potential therapeutic targets and have furthermore demonstrated that two classes of compounds significantly reduced virus replication, presumably via the inhibition of viral Pro and ACAT, respectively. Since NV Pro and ACAT play a critical role in viral replication, the hypothesis is advanced that agents capable of inhibiting these enzymes selectively are of potential therapeutic value. Thus, the long term goal of this program is the development of novel small molecule therapeutics against human noroviruses by advancing the active compounds through the stage prior to filing an IND application with the FDA. We have established the following specific aims for advancing our hit compounds into a drug candidate for preclinical development.
Specific Aim 1 : Utilize medicinal/combinatorial chemistry and molecular modeling to optimize two classes of compounds. The goal of this aim is to identify lead compounds that meet potency, selectivity, c log P, bioavailability, and other relevant parameters for drug development.
Aim 2. Conduct in vitro studies to establish the mechanism of action of two classes of compounds. We will also evaluate viral resistance to lead compounds by long-term treatment.
Aim 3. Conduct ADME/TOX and oral bioavailability studies to optimize the phamacokinetic parameters of selected lead compounds.
Aim 4. Demonstrate in vivo efficacy of lead compounds using the gnotobiotic pig model of human norovirus infection. Accomplishment of these specific aims will set the stage for conducting IND-enabling studies, including large-scale GMP synthesis of lead compounds, pharmacokinetics, GLP toxicology and safety pharmacology.

Public Health Relevance

Human noroviruses are now the leading cause of food- or water-borne gastroenteritis illnesses, but currently there are no commercially available vaccines or antivirals against them. Our studies aim at advancing our hit compounds into a drug candidate for preclinical development, which will have a significant impact on norovirus research and public health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI081891-05
Application #
8432063
Study Section
Special Emphasis Panel (ZAI1-MMT-M (J2))
Program Officer
Cassels, Frederick J
Project Start
2009-03-15
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2015-02-28
Support Year
5
Fiscal Year
2013
Total Cost
$895,635
Indirect Cost
$135,236
Name
Kansas State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
929773554
City
Manhattan
State
KS
Country
United States
Zip Code
66506
Shivanna, Vinay; Kim, Yunjeong; Chang, Kyeong-Ok (2014) Endosomal acidification and cathepsin L activity is required for calicivirus replication. Virology 464-465:287-95
Shivanna, Vinay; Kim, Yunjeong; Chang, Kyeong-Ok (2014) The crucial role of bile acids in the entry of porcine enteric calicivirus. Virology 456-457:268-78
Prior, Allan M; Zhang, Man; Blakeman, Nina et al. (2014) Inhibition of long chain fatty acyl-CoA synthetase (ACSL) and ischemia reperfusion injury. Bioorg Med Chem Lett 24:1057-61
Prior, Allan M; Gunaratna, Medha J; Kikuchi, Daisuke et al. (2014) Syntheses of 3-[(Alkylamino)methylene]-6-methylpyridine-2,4(1H,3H)-diones, 3-Substituted 7-Methyl-2H-pyrano[3,2-c]pyridine-2,5(6H)-dione Fluorescence Probes, and Tetrahydro-1H,9H-2,10-dioxa-9-azaanthracen-1-ones. Synthesis (Stuttg) 46:2179-2190
Mandadapu, Sivakoteswara Rao; Gunnam, Mallikarjuna Reddy; Galasiti Kankanamalage, Anushka C et al. (2013) Potent inhibition of norovirus by dipeptidyl *-hydroxyphosphonate transition state mimics. Bioorg Med Chem Lett 23:5941-4
Kim, Yunjeong; Mandadapu, Sivakoteswara Rao; Groutas, William C et al. (2013) Potent inhibition of feline coronaviruses with peptidyl compounds targeting coronavirus 3C-like protease. Antiviral Res 97:161-8
Mandadapu, Sivakoteswara Rao; Weerawarna, Pathum M; Prior, Allan M et al. (2013) Macrocyclic inhibitors of 3C and 3C-like proteases of picornavirus, norovirus, and coronavirus. Bioorg Med Chem Lett 23:3709-12
Prior, Allan M; Kim, Yunjeong; Weerasekara, Sahani et al. (2013) Design, synthesis, and bioevaluation of viral 3C and 3C-like protease inhibitors. Bioorg Med Chem Lett 23:6317-20
Takahashi, Daisuke; Hiromasa, Yasuaki; Kim, Yunjeong et al. (2013) Structural and dynamics characterization of norovirus protease. Protein Sci 22:347-57
Hua, Duy H (2013) Design, synthesis, and evaluation of bioactive small molecules. Chem Rec 13:60-9

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