Document text
Principal Investigator: Vaughn Vasil Smider
Organization: APPLIED BIOMEDICAL SCIENCE INSTITUTE
Fiscal Year: 2023
Award: $967,225
Funding agency: National Institute of Allergy and Infectious Diseases
Abstract
Targeted therapeutic agents range in size from very small organic molecules (100’s of Da) to
protein-based molecules like monoclonal antibodies (~150,000 Da). Small disulfide bonded
peptides have evolved in many species, including plants and animals, to have ideal
pharmacological properties including high affinity target binding, stability to proteases, heat and
other stresses. Such peptides include “cyclotides” or “knottins” which can inhibit enzymes, ion
channels, and GPCRs with high potency and are often the major active component of venoms
of many predator organisms. We have uncovered convergent evolution between ultralong third
complementary determining regions (CDR H3s) in the heavy chain of an unusual class of cow
antibodies and cyclotide/knottin peptides. We can produce these “knob” peptides in microbial
systems and they retain the binding and potency properties of the parent antibody. These tiny
peptide-based molecules are small (~4-6 kDa), highly stable, and can bind targets at
subnanomolar KD. We have already developed a panel of virus neutralizing knob peptides
against SARS-CoV-2 which bind unique epitopes, and some of which maintain high affinity
binding to various SARS-CoV-2 variants, including the recent ‘delta’ and ‘omicron’ strains. The
high stability, potency, and straightforward manufacturing path enables multiple routes of
administration, potentially including inhaled or intranasal delivery, which could be very important
prophylactic or treatment in the current or future coronavirus pandemic. Our goals in this project
are to further develop the technology to identify peptidic knob domains, expand our panel of
knobs against SARS-CoV-2 variants and other coronaviruses like MERS-CoV and SARS-CoV-
1, understand the structural basis of their binding, and validate their activity in vitro and in vivo.
The knobs identified here can potentially be used as monotherapy or combination therapy in the
current or a new coronavirus pandemic, and will be a valuable new therapeutic class to add to
the arsenal against coronavirus disease.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV variant><2019-nCoV variant forms><2019-nCoV variant strains><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Affinity><Animals><Antibodies><Antibody Binding Sites><Antibody Response><Antigen Binding Fragment><Antigenic Determinants><Antigens><Antiviral Agents><Antiviral Drugs><Antivirals><Binding><Binding Determinants><Blood Serum><Bovine Species><COVID><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 outbreak><COVID-19 pandemic><COVID-19 public health crisis><COVID-19 variant><COVID-19 variant forms><COVID-19 variant strains><COVID-19 virus><COVID19><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 outbreak><COVID19 pandemic><COVID19 public health crisis><COVID19 virus><CV-19><CV19><Cattle><Cessation of life><Clinical><Clinical Treatment Moab><CoV S protein><CoV disease><CoV emergence><CoV glycoprotein S><CoV pandemic><CoV spike glycoprotein><CoV spike protein><CoV-2><CoV2><Combined Modality Therapy><Coronaviridae><Coronavirus><Coronavirus glycoprotein S><Coronavirus spike protein><Death><Disease><Disease Outbreaks><Disease model><Disorder><Distant><Disulfides><E coli><E. coli><Electron Microscopy><Enzyme Inhibition><Epitopes><Escherichia coli><Esteroproteases><Evolution><Fab Fragments><Fab Immunoglobulins><Future><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G-Protein-Coupled Receptors><GPCR><Genetic Diversity><Genetic Variation><Goals><HIV><Human><Human Immunodeficiency Viruses><Immunity><Immunize><Immunoglobulin, F(ab) Fragment><In Vitro><Infection><Inhalation><Inhaling><Ion Channel><Ionic Channels><LAV-HTLV-III><Length><Libraries><Light><Lung diseases><Lymphadenopathy-Associated Virus><MAb Therapeutics><MERS><MERS corona virus><MERS coronavirus><MERS coronavirus disease><MERS virus><MERS-CoV><MERS-CoV disease><Membrane Channels><Metabolic Glycosylation><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 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><Molecular Evolution><Molecular Interaction><Monoclonal Antibodies><Multimodal Therapy><Multimodal Treatment><Organism><Outbreaks><Paratopes><Parents><Passive Immunotherapy><Patients><Pattern><Peptidases><Peptide Hydrolases><Peptides><Photoradiation><Plants><Production><Property><Prophylactic treatment><Prophylaxis><Protease Gene><Proteases><Proteinases><Proteins><Proteolytic Enzymes><Pulmonary Diseases><Pulmonary Disorder><Resistance><Respiratory Disease><Respiratory System Disease><Respiratory System Disorder><Risk><Rodent Diseases><Route><SARS><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS coronavirus disease><SARS-Associated Coronavirus><SARS-CO-V2><SARS-COVID-2><SARS-CoV><SARS-CoV disease><SARS-CoV-1><SARS-CoV-2><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 outbreak><SARS-CoV-2 pandemic><SARS-CoV-2 variant><SARS-CoV-2 variant forms><SARS-CoV-2 variant strains><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><Serum><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><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 coronavirus 2><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 outbreak><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Single Crystal Diffraction><Stress><System><Techniques><Technology><Therapeutic><Therapeutic Monoclonal Antibodies><Transmission><Variant><Variation><Venoms><Viral><Viral Activity><Viral Function><Viral Physiology><Virus><Virus-HIV><Work><Wuhan coronavirus><X Ray Crystallographies><X-Ray Crystallography><X-Ray Diffraction Crystallography><X-Ray/Neutron Crystallography><Xray Crystallography><anti-viral agents><anti-viral compound><anti-viral drugs><anti-viral medication><anti-viral therapeutic><anti-virals><antibody combining site><antiviral compound><antiviral medication><antiviral therapeutic><bovid><bovine><combination therapy><combined modality treatment><combined treatment><corona virus><corona virus disease><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><corona virus emergence><coronavirus S protein><coronavirus disease><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 outbreak><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease 2019 variant><coronavirus disease 2019 variant forms><coronavirus disease 2019 variant strains><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19><coronavirus disease-19 global pandemic><coronavirus disease-19 outbreak><coronavirus disease-19 pandemic><coronavirus disease-19 virus><coronavirus emergence><coronavirus infectious disease-19><coronavirus pandemic><coronavirus spike glycoprotein><cow><cross reactivity><disease of the lung><disorder model><disorder of the lung><disulfide bond><emergent CoV><emergent corona virus><emergent coronavirus><emerging CoV><emerging corona virus><emerging coronavirus><future pandemic><glycosylation><hCoV19><immunogen><in vitro activity><in vivo><inhibitor><life-threatening COVID><life-threatening COVID-19><life-threatening SARS-CoV-2><life-threatening coronavirus disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><living system><lung disorder><mAbs><manufacture><microbial><monoclonal Abs><monoclonal antibody drugs><multi-modal therapy><multi-modal treatment><nCoV><nCoV2><nano-molar><nanomolar><neutralizing antibody><new CoV><new corona virus><new coronavirus><new drug class><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><next pandemic><novel><novel CoV><novel corona virus><novel coronavirus><novel drug class><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><outbreak of SARS-CoV-2><pandemic><pandemic disease><parent><passive immune therapy><passive immunotherapeutics><pharmacologic><prophylactic><resistant><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><severe COVID><severe COVID-19><severe COVID19><severe SARS-CoV-2><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe acute respiratory syndrome coronavirus 2 variant><severe acute respiratory syndrome coronavirus 2 variant forms><severe acute respiratory syndrome coronavirus 2 variant strains><severe acute respiratory syndrome-CoV><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><small molecule><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic agent development><therapeutic development><therapeutic mAbs><tool><transmission process><variants of concern>