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Principal Investigator: ARUN K GHOSH
Organization: PURDUE UNIVERSITY
Fiscal Year: 2021
Award: $750,974
Funding agency: National Institute of Allergy and Infectious Diseases
Abstract
The main objective of this project is to advance our extensive preliminary results and develop
novel protease inhibitor drugs for the effective treatment of COVID-19. The COVID-19 pandemic,
caused by the highly transmissible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-
2), emerged in central China's Hubei Province, Wuhan in December 2019. The outbreak has
spread at an alarming rate, creating a catastrophic global health crisis the likes of which the world
has not witnessed in over 100 years. SARS-CoV-2 has spread to nearly every continent around
the globe and has affected over 4.8 million individuals with more than 380,000 deaths. Thus far,
there are no vaccines or approved effective drug treatments against COVID-19. The development
of antiviral agents is the foremost priority for reducing morbidity and mortality around the world.
SARS-CoV-2 encodes two classes of cysteine proteases, the 3-chymotrypsin-like protease
(3CLpro) and the papain-like protease (PLpro), which are critical for coronavirus replication.
These two proteases have been recognized as important targets for drug development against
COVID-19 and related pathogenic coronaviruses.
In our extensive collaborative work against SARS and MERS coronaviruses, we previously
developed and reported the development of a variety of covalent and non-covalent small-
molecule reversible inhibitors of SARS-CoV-3CLpro that showed significant antiviral activity. We
also demonstrated that PLpro is a significant drug target by developing the first non-covalent,
reversible and potent inhibitors of SARS-CoV-PLpro that show effective antiviral activity in cell
culture and in an animal model. We carried out structure-activity and extensive X-ray structural
studies to gain molecular insight into the 3CLpro and PLpro active sites of SARS, MERS and
most recently SARS-CoV-2. Furthermore, we have now generated a number of new small
molecule lead inhibitors of SARS-CoV-2 3CLpro and PLpro and determined several high-
resolution X-ray structures of SARS-CoV-2 3CLpro inhibitor complexes. This work forms the basis
of our proposed studies. We now plan to design, optimize and develop structurally novel drug-
like and broad-spectrum protease inhibitors that show favorable pharmacological profiles and low
toxicity. We will carry out a multidisciplinary research effort that will integrate X-ray structure-
guided design, iterative medicinal chemistry, molecular modeling, biochemical and biophysical
assays, antivirus and cell biological studies in combination with various physiochemical assays to
optimize compounds for preclinical development against COVID-19.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Active Sites><Affect><Animal Model><Animal Models and Related Studies><Anti-viral Drug Resistance><Anti-viral Drug Resistant><Antiproteases><Antiviral Agents><Antiviral Drug Resistance><Antiviral Drug Resistant><Antiviral Drugs><Antivirals><Assay><Binding Sites><Bioassay><Bioavailability><Biochemical><Biologic Assays><Biologic Availability><Biological><Biological Assay><Biological Availability><Biophysics><COVID crisis><COVID epidemic><COVID pandemic><COVID-19><COVID-19 crisis><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 prevention><COVID-19 public health crisis><COVID-19 therapy><COVID-19 treatment><COVID-19 virus><COVID19><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 pandemic><COVID19 prevention><COVID19 public health crisis><COVID19 therapy><COVID19 treatment><COVID19 virus><CV-19><CV19><Caspase><Caspase Gene><Cell Body><Cell Culture Techniques><Cell-Death Protease><Cells><Cellular biology><Cessation of life><China><Chymase><CoV-2><CoV2><Combining Site><Common Rat Strains><Complex><Contracting Opportunities><Contracts><Coronaviridae><Coronavirus><Crystallization><Cysteine Endopeptidases><Cysteine Protease><Cysteine Proteinases><Death><Development><Disease Management><Disease Outbreaks><Disorder Management><Drug Design><Drug Targeting><Drug Therapy><Drug resistance><Drugs><Endopeptidase Inhibitors><Enzyme Inhibition><Enzyme Kinetics><Epitheliasin Gene><Esteroproteases><Exhibits><Future><Generations><Hospitals><ICE-like protease><Individual><Infection><Interdisciplinary Research><Interdisciplinary Study><Japan><Laboratories><Lead><Ligand Binding><Ligands><MERS><MERS corona virus><MERS coronavirus><MERS coronavirus disease><MERS virus><MERS-CoV><MERS-CoV disease><MMCP-1><Mainland China><Medication><Medicinal Chemistry><Medicine><Middle East Respiratory Syndrome><Middle East Respiratory Syndrome CoV disease><Middle East Respiratory Syndrome Corona Virus><Middle East Respiratory Syndrome Coronavirus><Middle East Respiratory Syndrome Virus><Middle East Respiratory Syndrome coronavirus disease><Middle East Respiratory Syndrome-CoV><Middle Eastern Respiratory Syndrome><Middle Eastern Respiratory Syndrome CoV disease><Middle Eastern Respiratory Syndrome Corona virus><Middle Eastern Respiratory Syndrome Coronavirus><Middle Eastern Respiratory Syndrome Virus><Middle Eastern Respiratory Syndrome coronavirus disease><Middle Eastern Respiratory Syndrome-CoV><Molecular><Molecular Modeling Nucleic Acid Biochemistry><Molecular Modeling Protein/Amino Acid Biochemistry><Molecular Models><Morbidity><Morbidity - disease rate><Multidisciplinary Collaboration><Multidisciplinary Research><NCI Organization><NIAID><National Cancer Institute><National Institute of Allergy and Infectious Disease><Oral><Outbreaks><PRSS10><Papain><Pathogenicity><Pb element><Peptidase Inhibitors><Peptidases><Peptide Hydrolase Inhibitors><Peptide Hydrolases><Peptide Peptidohydrolase Inhibitors><Pharmaceutic Chemistry><Pharmaceutic Preparations><Pharmaceutical Chemistry><Pharmaceutical Preparations><Pharmacological Study><Pharmacology><Pharmacology Study><Pharmacotherapy><Physiologic Availability><Polyproteins><Process><Property><Protease Antagonists><Protease Gene><Protease Inhibitor><Proteases><Proteinase Inhibitors><Proteinases><Proteins><Proteolytic Enzymes><Province><Public Health><Rat><Rats Mammals><Rattus><Reactive Site><Reporting><Research><Resistance profile><Resistant profile><Resolution><Roentgen Rays><SARS><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS coronavirus disease><SARS-Associated Coronavirus><SARS-CoV><SARS-CoV disease><SARS-CoV-2><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 inhibitor><SARS-CoV-2 pandemic><SARS-CoV-2 therapy><SARS-CoV-2 treatment><SARS-CoV2><SARS-CoV2 epidemic><SARS-CoV2 pandemic><SARS-Related Coronavirus><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome CoV disease><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe Acute Respiratory Syndrome coronavirus disease><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 inhibitor><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Single Crystal Diffraction><Structure><TMPRSS2><TMPRSS2 gene><Tokyo><Toxic effect><Toxicities><Uncertainty><Universities><Vaccines><Viral><Viral Drug Resistance><Virus><Virus Replication><Work><Wuhan coronavirus><X Ray Crystallographies><X-Radiation><X-Ray Crystallography><X-Ray Diffraction Crystallography><X-Ray Radiation><X-Ray/Neutron Crystallography><X-ray><Xray><Xray Crystallography><anti-viral agents><anti-viral drugs><anti-virals><base><biophysical foundation><biophysical principles><biophysical sciences><block SARS-CoV-2><block severe acute respiratory syndrome coronavirus 2><cell biology><cell culture><chymase-1><chymotrypsin-like protease><clinical efficacy><computational studies><computer studies><corona virus><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus disease 2019><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 prevention><coronavirus disease 2019 public health crisis><coronavirus disease 2019 therapy><coronavirus disease 2019 treatment><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><cystein protease><cystein proteinase><cysteine endopeptidase><design><designing><developmental><doubt><drug development><drug resistant><drug treatment><drug/agent><effective therapy><effective treatment><experience><global health><hCoV19><heavy metal Pb><heavy metal lead><improved><inhibit SARS-CoV-2><inhibit severe acute respiratory syndrome coronavirus 2><inhibitor><inhibitor/antagonist><insight><lead optimization><mast cell protease><mast cell protease 1><mast cell protease I><mast cell proteinase-1><model of animal><model organism><molecular modeling><mortality><multidisciplinary><nCoV2><nano-molar><nanomolar><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel therapeutics><novel therapy><overexpress><overexpression><pandemic><pandemic disease><pre-clinical><pre-clinical development><pre-clinical study><preclinical><preclinical development><preclinical study><prevent COVID-19><prevent COVID19><prevent coronavirus disease 2019><public health relevance><replicase><resistance to Drug><resistance to anti-viral><resistance to antiviral><resistant to Drug><resistant to anti-viral><resistant to antiviral><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe acute respiratory syndrome coronavirus 2 therapy><severe acute respiratory syndrome coronavirus 2 treatment><severe acute respiratory syndrome-CoV><skeletal muscle protease><small molecule><therapeutic candidate><treat COVID-19><treat COVID19><treat SARS-CoV-2><treat coronavirus disease 2019><treat severe acute respiratory syndrome coronavirus 2><viral multiplication><viral replication><virology><virus multiplication>