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Principal Investigator: Kyeong-Ok Chang
Organization: KANSAS STATE UNIVERSITY
Fiscal Year: 2024
Award: $773,323
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
Middle East respiratory syndrome coronavirus (MERS-CoV) emerged suddenly in 2012 as the cause of
severe respiratory illness in humans. Despite the high mortality rate (~ 40%) and the significant potential for a
public health emergency, there are no FDA-approved vaccines or antiviral drugs for MERS. Consequently, there
is an urgent and unmet need for the development of small-molecule drugs to control MERS-CoV infection.
Furthermore, members of the Merbecovirus and Sarbecovirus subgenera within the Betacoronavirus genus pose
a high risk of future spillover into humans. However, efforts to develop general strategies to mitigate the impact
of future pandemics have been limited. Coronavirus 3C-like protease (3CLpro) is a well-characterized
therapeutic target as it processes most cleavage sites on virus polyproteins and is essential for virus replication.
Multiple series of 3CLpro inhibitors with potent activity against MERS-CoV and in vivo efficacy in mouse models
were reported by our group. However, these compound series are parenterally administrable with limited oral
bioavailability. Hypothesize of this project is that inhibitors exploiting the exquisite stereochemical control and
multiple diversity sites afforded by the 1,3,2-oxazaphospholidin-3-one scaffold (series I and II) and decorated
with a novel transition state analog endowed with favorable oral bioavailability can serve as a launching pad for
the development of orally bioavailable MERS-CoV-specific antivirals. As these inhibitors can engage in binding
interactions with the Sn and Sn' pockets of various coronavirus 3CLpros, the scaffold provides a versatile platform
for merbecoviruses and sarbecoviruses. Aims of this project are 1) Conduct iterative structure-guided design,
synthesis, and multiparameter optimization of inhibitors for MERS-CoV; 2) Conduct biochemical, structural, and
virological studies to characterize and prioritize analogs for MERS-CoV 3CLpro and conduct structure-activity
relationship studies with the generated series for merbecovirus/sarbecovirus 3CLpros; and 3) Demonstrate in
vivo efficacy of optimized leads in a mouse model of MERS-CoV infection. The overarching goal of this project
is the identification of an orally bioavailable preclinical candidate and 1-2 backup compounds based on inhibitor
series (I and II) for MERS-CoV infection, and the exploration and utilization of the generated inhibitors against
the 3CLpros of merbecoviruses and sarbecoviruses.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Anti-viral Agents><Antiproteases><Assay><Bats><Binding><Bioassay><Bioavailability><Biochemical><Biological Assay><Biological Availability><COVID-19 virus><COVID19 virus><Category C pathogen><Category C priority pathogen><Cell Body><Cell Culture Techniques><Cells><Cellular Assay><Characteristics><Chemicals><Chiroptera><CoV emergence><CoV-2><CoV2><Coronaviridae><Coronaviridae Infections><Coronavirus><Coronavirus Infections><Crystallographies><Crystallography><Death Rate><Development><Disease><Disease Outbreaks><Disorder><Dose><Drug resistance><Drugs><Endopeptidase Inhibitors><Endowment><Enzyme Gene><Enzymes><Esteroproteases><Evaluation><FDA approved><Funding><Future><Goals><HCoV><Human><In Vitro><Lead><Lytotoxicity><MERS><MERS corona virus><MERS coronavirus><MERS coronavirus disease><MERS virus><MERS-CoV><MERS-CoV disease><Medication><Merbecovirus><Middle East><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 East Respiratory Virus><Middle East Respiratory coronavirus><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><Modern Man><Molecular Interaction><NIAID><National Institute of Allergy and Infectious Disease><Oral><Outbreaks><Pb element><Peptidase Inhibitors><Peptidases><Peptide Hydrolase Inhibitors><Peptide Hydrolases><Peptide Peptidohydrolase Inhibitors><Pharmaceutical Preparations><Physiologic Availability><Polyproteins><Process><Property><Protease Antagonists><Protease Gene><Protease Inhibitor><Proteases><Proteinase Inhibitors><Proteinases><Proteolytic Enzymes><Public Health><Receptor Protein><Reporter><Reporting><Republic of Korea><Research><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-CoV2><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><Sarbecovirus><Saudi Arabia><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 coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Site><South Korea><Structure><Structure-Activity Relationship><Vaccines><Viral><Virus><Virus Replication><World Health Organization><Wuhan coronavirus><analog><anti-viral compound><anti-viral drugs><anti-viral medication><anti-viral therapeutic><anti-virals><beta CoV><beta coronavirus><betaCoV><betacoronavirus><cell assay><cell culture><cell cultures><chemical structure function><corona virus><corona virus emergence><coronavirus disease 2019 virus><coronavirus disease-19 virus><coronavirus emergence><coronavirus of pandemic concern><coronavirus of pandemic potential><coronavirus with pandemic potential><cytotoxicity><design><designing><developmental><drug resistant><drug/agent><emergent CoV><emergent corona virus><emergent coronavirus><emerging CoV><emerging corona virus><emerging coronavirus><future pandemic><hCoV19><heavy metal Pb><heavy metal lead><high risk><human CoV><human corona virus><human coronavirus><improved><in vivo><indexing><inhibitor><member><meter><mortality rate><mortality ratio><mouse model><murine model><nCoV><nCoV2><new CoV><new corona virus><new coronavirus><next pandemic><novel><novel CoV><novel corona virus><novel coronavirus><pandemic coronavirus><pandemic threat coronavirus><pharmacologic><pre-clinical><preclinical><public health emergency><receptor><resistance to Drug><resistant to Drug><respiratory><scaffold><scaffolding><screening><screenings><severe acute respiratory syndrome-CoV><small molecule><structural determinants><structural factors><structure function relationship><synergism><therapeutic target><viral multiplication><viral replication><virus multiplication><β CoV><β coronavirus><βCoV>