Development of neutralizing nanobodies against SARS-CoV-2
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Principal Investigator: Mitchell Ho Organization: DIVISION OF BASIC SCIENCES - NCI Fiscal Year: 2020 Award: $416,151 Funding agency: National Cancer Institute In FY20, Dr Ho has evaluated the current status and challenges for developing antibody therapeutics targeting SARS-Cov-2 and wrote a review/perspective article [Ho Antibody Therapeutics 2020; PMID: 32566896]. SARS-CoV-2 gains entry to human cells through its spike (S) protein binding to angiotensin-converting enzyme 2 (ACE2). Therefore, the receptor binding domain (RBD) of the S protein is the primary target for neutralizing antibodies. Selection of broad-neutralizing antibodies against SARS-CoV-2 and SARS-CoV is attractive and might be useful for treating not only COVID-19 but also future SARS-related CoV infections. Broad-neutralizing antibodies have been reported to target a conserved region in the RBD of the S1 subunit. The S2 subunit required for viral membrane fusion might be another target. A cocktail strategy combining two (or more) antibodies that recognize different parts of the viral surface that interact with human cells might be the most effective. In FY2020, our pilot screen in the Ho lab using phage display technology has identified a panel of camel nanobodies that might recognize diverse conformations of the RBD. Some might bind an "open" conformation of the RBD, which might block the interaction with the ACE2 on human cell, while others might bind a "close" conformation, which might lock its conformation in the off state. Ongoing studies will establish our nanobodies as a new family of anti-viral drugs for treating COVID-19 and potentially future coronavirus infections in humans. Terms: <2019 novel coronavirus><2019-nCoV><Angiotensin Converting Enzyme><Angiotensin I-Converting Enzyme><Antibodies><Antiviral Agents><Antiviral Drugs><Antivirals><Bacteriophages><Binding><Binding Proteins><Biological><CD143 Antigens><COVID-19><COVID19><Camels><Carboxycathepsin><Cell Body><Cells><Coronaviridae><Coronaviridae Infections><Coronavirus><Coronavirus Infections><Development><Dipeptidyl Peptidase A><Family><Future><Human><Infection><Kininase A><Kininase II><Libraries><Ligand Binding Protein><Ligand Binding Protein Gene><MERS corona virus><MERS coronavirus><MERS virus><MERS-CoV><Membrane Fusion><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><Modern Man><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><Peptidyl-Dipeptidase A><Phage Display><Phages><Protein Binding><Proteins><Reporting><Research><SARS><SARS Virus><SARS corona virus><SARS coronavirus><SARS coronavirus disease><SARS-Associated Coronavirus><SARS-CoV><SARS-CoV disease><SARS-CoV-2><SARS-CoV2><SARS-Related Coronavirus><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 Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe Acute Respiratory Syndrome coronavirus disease><Severe acute respiratory syndrome coronavirus 2><Shark><Structure><Surface><Technology><Therapeutic antibodies><Viral><Wuhan coronavirus><anti-viral agents><anti-viral drugs><anti-virals><bacterial virus><bound protein><conformation><conformational state><corona virus><corona virus disease 2019><coronavirus disease 2019><developmental><global health><nanobodies><nanobody><neutralizing antibody><novel><pandemic><pandemic disease><receptor binding><receptor bound><sdAb><severe acute respiratory syndrome-CoV><single domain antibodies><therapeutic target>