Kidney Microphysiological Analysis Platforms (MAP) to Explore SARS-CoV-2 Receptors and Inhibitors. A supplement to Parent Grant: Kidney Microphysiological Analysis Platforms (MAP) to Optimize Function

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Principal Investigator: JOSEPH VINCENT BONVENTRE
Organization: BRIGHAM AND WOMEN'S HOSPITAL
Fiscal Year: 2020
Award: $251,531
Funding agency: National Center for Advancing Translational Sciences

Abstract
Coronavirus disease 2019 (COVID-19) has reached pandemic proportions. Pulmonary and
kidney disease are highly prevalent serious consequences of infection with SARS-CoV-2. Kidney
Injury Molecule-1 (KIM-1) was identified by Drs Bonventre and Ichimura as the most upregulated
protein in the injured kidney proximal tubule. KIM-1, also called TIM-1, is a receptor for hepatitis
A, Ebola, Dengue and possibly SARS-CoV1 viruses. We hypothesize that KIM-1 is a receptor
for SARS-CoV-2 both in renal tubule epithelial cells and in airway epithelial cells and that
JB1, our newly discovered small molecule inhibitor of KIM-1, and/or nanodisc-
incorporated KIM-1 ectodomain can be prophylactic and therapeutic agents for COVID-19.
We also hypothesize that we can use the high-affinity binding of KIM-1 and ACE2 to the
virus to create novel diagnostic devices for the virus. In Specific Aim 1 we will characterize
the role of KIM-1 in promoting SARS-CoV-2 entry into kidney and lung epithelia using kidney
microphysiological analysis platforms (MAPs) on chip and develop an ultrasensitive chip for the
high-throughput evaluation of potential SARS-CoV-2 binding inhibitors. KIM-1 and ACE2
mediated endocytosis of SARS-CoV-2 biomimetic viruses (virosomes) will be compared in kidney
and lung epithelial cells. We will evaluate the effects of KIM-1-mediated spike proteins or
biomimetic virus cellular adhesion and uptake on production of paracrine factors which activate
endothelial cells using a kidney-lung MAP. In order to understand binding and/or uptake kinetics
of SARS-CoV-2 and characterize potential inhibitors we will develop an ultrasensitive
nanoplasmonic triplets-based rapid lateral flow diagnostic chip for a rapid and sensitive inhibition
assay using the kidney-lung MAP. This approach can also be used for point of care diagnostic
testing for the virus. In Specific Aim 2 we will evaluate the efficacy of JB1, soluble KIM-1
ectodomain and nanodisc-incorporated KIM-1 or ACE2 to inhibit binding and internalization of
SARS-CoV-2 biomimetic viruses by kidney and lung cells using an integrated lung-kidney MAP
on chip. Potential inhibitors will be tested to evaluate whether they compete with S-protein and/or
biomimetic virus binding and reduce IL-6 production. Binding affinity and kinetics between KIM-1
variants or ACE2 either as free ectodomains or incorporated into nanodiscs and the Spike protein
will be measured using MicroScale Thermophoresis (MST) and Biolayer Interferometry.

Terms: <2019 novel coronavirus><2019-nCoV><A549><Affinity><Angiotensin Converting Enzyme><Angiotensin I-Converting Enzyme><Animals><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antiinflammatories><Antiinflammatory Agents><Apoptotic><Assay><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Bedside Testings><Binding><Binding Proteins><Bioassay><Biologic Assays><Biological Assay><Biological Mimetics><Biomimetics><Bleo><Bleomycin><Breakbone Fever Virus><CD143 Antigens><COVID-19><COVID19><Carboxycathepsin><Cell Adhesion><Cell Body><Cell Surface Glycoproteins><Cells><Cellular Adhesion><Dengue><Dengue Virus><Dengue fever virus><Devices><Diagnostic><Diagnostic tests><Dipeptidyl Peptidase A><Disease><Disorder><Ebola><Endocytosis><Endothelial Cells><Endothelium><Epithelial><Epithelial Cells><Epithelium><Epithelium Part><Evaluation><Exposure to><External Domain><Extracellular Domain><Family member><HAV cellular receptor><HPGF><Hepatic Cells><Hepatic Parenchymal Cell><Hepatitis A><Hepatocyte><Hepatocyte-Stimulating Factor><Human><Hybridoma Growth Factor><IFN-beta 2><IFNB2><IL-6><IL6 Protein><Immune Globulins><Immunoglobulins><In Vitro><Infection><Injury to Kidney><Interferometry><Interleukin-6><Kidney><Kidney Diseases><Kidney Tubules><Kidney Urinary System><Kinetics><Kininase A><Kininase II><Label><Lateral><Ligand Binding Protein><Ligand Binding Protein Gene><Ligands><Liver Cells><Lung><Lung Adenocarcinoma><Lung Respiratory System><Lung diseases><MGI-2><Maintenance><Measurement><Measures><Mediating><Membrane Glycoproteins><Microfabrication><Microfluidics><Modeling><Modern Man><Molecular Interaction><Monkeys><Mucins><Mucus Glycoprotein><Myeloid Differentiation-Inducing Protein><NSCLC><NSCLC - Non-Small Cell Lung Cancer><Nephropathy><Non-Small Cell Lung Cancer><Non-Small-Cell Lung Carcinoma><Non-specific crossreacting antigens><Nonsmall Cell Lung Carcinoma><Peptidyl-Dipeptidase A><Phagocytosis><Physiologic><Physiological><Plasmacytoma Growth Factor><Production><Protein Binding><Proteins><Proximal Kidney Tubules><Pulmonary Diseases><Pulmonary Disorder><Receptor Protein><Renal Cell><Renal Disease><Renal tubule structure><Reporting><Respiratory Disease><Respiratory System Disease><Respiratory System Disorder><Role><SARS><SARS coronavirus disease><SARS-CoV disease><SARS-CoV-2><SARS-CoV2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related coronavirus 2><Severe Acute Respiratory Syndrome><Severe Acute Respiratory Syndrome CoV disease><Severe Acute Respiratory Syndrome coronavirus disease><Severe acute respiratory syndrome coronavirus 2><Surface Glycoproteins><System><T-Cells><T-Lymphocyte><Testing><Therapeutic Agents><Time><Triplet Multiple Birth><Triplets><Variant><Variation><Viral Receptor><Virosomes><Virus><Virus Receptors><Work><Wuhan coronavirus><airway epithelium><antiinflammatory><base><bound protein><bronchial epithelium><carcinoembryonic antigen-related cell adhesion molecules><corona virus disease 2019><coronavirus disease 2019><coronavirus receptor><cytokine release syndrome><cytokine storm><disease of the lung><disorder of the lung><hepatitis A virus cellular receptor><hepatitis A virus receptor><inhibitor><inhibitor/antagonist><interferon beta 2><kidney cell><kidney disorder><kidney injury><kidney injury molecule 1><lung disorder><nano disk><nano-plasmonic><nanodisk><nanoplasmonic><new diagnostics><new technology><next generation diagnostics><nonsmall cell lung cancer><novel><novel diagnostics><novel technologies><oxidized lipid><pandemic><pandemic disease><paracrine><parent grant><phosphatidylserine receptor><point of care testing><point-of-care diagnostics><prevent><preventing><prophylactic><pulmonary><rat KIM-1 protein><receptor><renal><renal KIM-1><renal disorder><renal injury><renal proximal tubule><renal tubule><response><side effect><small molecule><small molecule inhibitor><social role><stem cell biology><therapeutic candidate><thymus derived lymphocyte><uptake><µfluidic>