Document text
Principal Investigator: Kyeong-Ok Chang
Organization: KANSAS STATE UNIVERSITY
Fiscal Year: 2022
Award: $735,037
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
Human coronaviruses generally cause the common cold, a mild upper respiratory illness, however, global
outbreaks of new human coronavirus infections with severe respiratory disease have periodically emerged from
animals. These include Severe Acute Respiratory coronavirus (SARS-CoV), Middle East respiratory syndrome
coronavirus (MERS-CoV) and, most recently, SARS-CoV-2, the causative agent of coronavirus disease 2019
(COVID-19). Currently, there are no licensed vaccines or antiviral drugs against these viruses, underscoring an
urgent need for the development of preventive and therapeutic measures against coronaviruses. Coronavirus
genomes encode large polyproteins which are processed by a 3C-like protease (3CLpro) and a papain-like
protease. Both proteases are essential for viral replication, making them attractive targets for drug development.
Our foray in this area has resulted in the discovery of broad-spectrum inhibitors of multiple viruses, including
coronaviruses and noroviruses that encode 3CLpro, as well as the first demonstration of clinical efficacy by a
feline coronavirus 3CLpro inhibitor. Recently, we have demonstrated that a dipeptidyl series of compounds
potently inhibit human coronaviruses, including MERS-CoV and SARS-CoV-2 in cell culture, and display in vivo
efficacy in the DPP4-KI mouse model of MERS-CoV infection. The antiviral target of the compounds was
validated by obtaining high resolution crystal structures 3CLpro-inhibitor complexes from SARS-CoV, SARS-
CoV-2 and MERS-CoV. We hypothesize herein that the identified series can serve as a launching pad for the
development of SARS-CoV-2-specific antivirals. The immediate and overarching goal of the proposed studies is
to further optimize the pharmacological activity PK parameters of identified lead inhibitors of SARS-CoV-2
3CLpro and the demonstration of in vivo efficacy against SARS-CoV-2. The expected outcome of our studies is
the selection of a preclinical candidate (and 1-2 backup compounds) that is well-suited to conducting further
preclinical studies, ultimately leading to the development of a COVID-19-specific antiviral therapeutic.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ACE2><Acute Nasopharyngitis><Adenoviridae><Adenoviruses><Adopted><Animal Model><Animal Models and Related Studies><Animals><Antiproteases><Antiviral Agents><Antiviral Drugs><Antivirals><Area><Assay><Back><Binding><Bioassay><Biochemical><Biologic Assays><Biological Assay><COVID-19><COVID-19 genome><COVID-19 infection><COVID-19 predisposition><COVID-19 susceptibility><COVID-19 therapy><COVID-19 treatment><COVID-19 virus><COVID-19 virus genome><COVID-19 vulnerability><COVID19><COVID19 genome><COVID19 infection><COVID19 therapy><COVID19 treatment><COVID19 virus><COVID19 virus genome><CV-19><CV19><Cell Body><Cell Culture Techniques><Cells><Chemicals><China><CoV-2><CoV2><Common Cold><Complex><Coronaviridae><Coronaviridae Infections><Coronavirus><Coronavirus Infections><Coronavirus disease 2019 predisposition><Coronavirus disease 2019 susceptibility><Coronavirus disease 2019 vulnerability><Crystallization><Development><Disease><Disease Outbreaks><Disorder><Dorsum><Drug Design><Drug Targeting><Drugs><Elements><Endopeptidase Inhibitors><Enzyme Gene><Enzymes><Esteroproteases><Family><Feline Coronavirus><Feline Enteric Coronavirus><Genome><Goals><HCoV><Histopathology><Human><In Vitro><K-18><K-18 conjugate><K18><K18 combination><KI mice><Knock-in><Knock-in Mouse><Lead><Lung><Lung Respiratory System><MERS corona virus><MERS coronavirus><MERS virus><MERS-CoV><Mainland China><Measures><Medication><Medicinal Chemistry><Mice><Mice Mammals><Middle East Respiratory Syndrome Corona Virus><Middle East Respiratory Syndrome Coronavirus><Middle East Respiratory Syndrome Virus><Middle East Respiratory Syndrome-CoV><Middle Eastern Respiratory Syndrome Corona virus><Middle Eastern Respiratory Syndrome Coronavirus><Middle Eastern Respiratory Syndrome Virus><Middle Eastern Respiratory Syndrome-CoV><Modeling><Modern Man><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><Murine><Mus><Norovirus><Norwalk-like Viruses><Outbreaks><Outcome><Papain><Pathogenicity><Pb element><Peptidase Inhibitors><Peptidases><Peptide Hydrolase Inhibitors><Peptide Hydrolases><Peptide Peptidohydrolase Inhibitors><Permeability><Pharmaceutic Chemistry><Pharmaceutic Preparations><Pharmaceutical Chemistry><Pharmaceutical Preparations><Pharmacology><Polyproteins><Predisposed to COVID-19><Predisposed to SARS-CoV-2><Predisposed to Severe acute respiratory syndrome coronavirus 2><Preventive><Process><Protease Antagonists><Protease Gene><Protease Inhibitor><Proteases><Proteinase Inhibitors><Proteinases><Proteolytic Enzymes><Public Health><RNA Viruses><Receptor Protein><Research><Resolution><Respiratory Disease><Respiratory System Disease><Respiratory System Disorder><Risk><Roentgen Rays><SARS Coronavirus 2 Protease><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS-Associated Coronavirus><SARS-CO-V2><SARS-COVID-2><SARS-CoV><SARS-CoV-1><SARS-CoV-2><SARS-CoV-2 genome><SARS-CoV-2 infection><SARS-CoV-2 inhibitor><SARS-CoV-2 predisposition><SARS-CoV-2 protease><SARS-CoV-2 susceptibility><SARS-CoV-2 therapy><SARS-CoV-2 treatment><SARS-CoV-2 vulnerability><SARS-CoV2><SARS-CoV2 genome><SARS-CoV2 infection><SARS-Related Coronavirus><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Series><Severe Acute Respiratory Coronavirus><Severe Acute Respiratory Coronavirus 2><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 CoV 2><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><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 infection><Severe acute respiratory syndrome coronavirus 2 inhibitor><Severe acute respiratory syndrome coronavirus 2 predisposition><Severe acute respiratory syndrome coronavirus 2 susceptibility><Severe acute respiratory syndrome coronavirus 2 vulnerability><Severe acute respiratory syndrome related corona virus 2><Structure><Structure-Activity Relationship><Therapeutic><Time><Transgenic Organisms><Upper Respiratory Infections><Upper Respiratory Tract Infection><Vaccines><Viral><Virus><Virus Replication><Wuhan coronavirus><X-Radiation><X-Ray Radiation><X-ray><Xray><analog><angiotensin converting enzyme 2><angiotensin converting enzyme II><anti-viral agents><anti-viral compound><anti-viral development><anti-viral drug development><anti-viral drugs><anti-viral efficacy><anti-viral medication><anti-viral therapeutic><anti-viral therapeutic development><anti-viral therapy development><anti-virals><antiviral compound><antiviral development><antiviral drug development><antiviral efficacy><antiviral medication><antiviral therapeutic><antiviral therapeutic development><antiviral therapy development><base><block SARS-CoV-2><block severe acute respiratory syndrome coronavirus 2><cell culture><cell cultures><chemical structure function><clinical candidate><clinical development><clinical efficacy><conformation><conformational state><corona virus><corona virus disease 2019><coronavirus disease 2019><coronavirus disease 2019 genome><coronavirus disease 2019 infection><coronavirus disease 2019 therapy><coronavirus disease 2019 treatment><coronavirus disease 2019 virus><coronavirus disease 2019 virus genome><coronavirus disease-19><coronavirus disease-19 virus><coronavirus infectious disease-19><design><designing><develop therapy><developing anti-viral agent><developing anti-viral drug><developing anti-viral therapeutic><developing anti-viral therapy><developing antiviral agent><developing antiviral drug><developing antiviral therapeutic><developing antiviral therapy><developmental><drug candidate><drug development><drug/agent><efficacy study><hCoV19><heavy metal Pb><heavy metal lead><human CoV><human corona virus><human coronavirus><improved><in vivo><indexing><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><inhibit SARS-CoV-2><inhibit severe acute respiratory syndrome coronavirus 2><inhibitor><intervention development><knockin><knockin mice><lead optimization><lead series><model of animal><model organism><mouse model><murine model><nCoV2><novel><pre-clinical><pre-clinical study><preclinical><preclinical study><predisposed to Coronavirus disease 2019><pulmonary><receptor><respiratory><scaffold><scaffolding><screening><severe acute respiratory syndrome coronavirus 2 genome><severe acute respiratory syndrome coronavirus 2 protease><severe acute respiratory syndrome coronavirus 2 therapy><severe acute respiratory syndrome coronavirus 2 treatment><severe acute respiratory syndrome-CoV><small molecule inhibitor><structure function relationship><susceptible to COVID-19><susceptible to Coronavirus disease 2019><susceptible to SARS-CoV-2><susceptible to Severe acute respiratory syndrome coronavirus 2><therapy development><transgenic><treat COVID-19><treat COVID19><treat SARS-CoV-2><treat coronavirus disease 2019><treat severe acute respiratory syndrome coronavirus 2><treatment development><viral multiplication><viral replication><virus multiplication>