Document text
Principal Investigator: Carole Bewley
Organization: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
Fiscal Year: 2024
Award: $621,127
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
The long-term goals of our project "HIV Neutralization Inhibitors: Engineering, characterization, and functions" are to identify and engineer protein and small molecule therapeutics, probes and vaccine immunogens that can be translated for the treatment and long-acting inhibition of HIV/AIDS. Though great progress has been achieved in developing treatments for and extending the life expectancies of HIV infected individuals, we do not have a cure or vaccine for this disease and many challenges remain including the development of drug resistance to currently used therapeutics, the high cost and availability of treatment, and the need for prevention strategies that are available to all. Among envelope viruses, the HIV spike protein in particular is unique in that its heterotrimeric structure is shrouded in a dense network of high-mannose oligosaccharides, now known as the ‘glycan shield’. Paradoxically, the carbohydrates that comprise the glycan shield are human glycans that are attached during translation and maturation of the viral genome. This leads to shielding of the virus from the immune system and complicates vaccine design and development. Because the high-mannose glycan shield is unique to viral proteins, mannose-binding lectins can potently inhibit HIV replication and infection. Thus, one subproject in our research group involves engineering of carbohydrate-binding proteins that specifically target the glycan shield of enveloped viruses such as HIV and coronaviruses. We have established proof of concept for our approaches (submitted for publication) and current work includes design and construction of bispecific antibody chimeras to rationally target multiple sites on the envelope proteins. Other subprojects include discovery of natural product inhibitors and peptide-based probes of HIV-1cell entry, and structural and mechanistic studies of HIV-1 Envelope-coreceptor interactions.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><AIDS Virus><AIDS/HIV><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Antigens><Bi-specific antibodies><Bifunctional Antibodies><Binding Sites><Biochemical><Bispecific Antibodies><COVID-19 virus><COVID19 virus><Carbohydrates><CoV-2><CoV2><Combining Site><Coronaviridae><Coronavirus><Cryo-electron Microscopy><Cryoelectron Microscopy><D-Mannose><Development><Disease><Disorder><Drug resistance><Electron Cryomicroscopy><Engineering><Envelope Protein><Finding natural products><Foundations><Glycans><Glycoproteins><Goals><HCV><HIV><HIV Envelope Glycoprotein gp120><HIV Envelope Protein gp120><HIV env Protein gp120><HIV-1><HIV-I><HIV/AIDS><HIV1><HTLV-III gp120><Hepatitis C virus><Human><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human immunodeficiency virus 1><Immune system><Individual><Infection><LAV-HTLV-III><Life Expectancy><Local Microbicides><Lymphadenopathy-Associated Virus><Mannan-Binding Lectin><Mannan-Binding Protein><Mannopyranose><Mannopyranoside><Mannose><Mannose Binding Lectin><Mannose-Binding Protein><Mannose-Specific Lectin><Mediating><Modern Man><NMR Spectrometer><NMR Spectroscopy><Natural product discovery><Oligosaccharides><Peptides><Polysaccharides><Preventative strategy><Prevention strategy><Preventive strategy><Protein Engineering><Proteins><Publications><Reactive Site><Receptor Protein><Research><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Scientific Publication><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-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><Single Crystal Diffraction><Site><Structure><Therapeutic><Therapeutic Uses><Translating><Translations><Vaccine Design><Vaccines><Viral><Viral Gene Products><Viral Gene Proteins><Viral Genome><Viral Proteins><Virus><Virus-HIV><Work><Wuhan coronavirus><X Ray Crystallographies><X-Ray Crystallography><X-Ray Diffraction Crystallography><X-Ray/Neutron Crystallography><Xray Crystallography><bsAb><carbohydrate binding protein><carbohydrate receptor><chimeric antibody><corona virus><coronavirus disease 2019 virus><coronavirus disease-19 virus><cost><cryo-EM><cryoEM><cryogenic electron microscopy><design><design and construct><design and construction><designing><develop a vaccine><develop drug resistance><develop vaccines><development of a vaccine><developmental><drug resistance development><drug resistant><env Antigens><env Gene Products><env Polyproteins><env Protein><genetic protein engineering><gp120><gp120 ENV Glycoprotein><gp120(HIV)><hCoV19><immunogen><in vivo><inhibitor><nCoV2><novel><nuclear magnetic resonance spectroscopy><protein bound carbohydrate><protein design><receptor><receptor binding><receptor bound><resistance to Drug><resistant to Drug><small molecular inhibitor><small molecule><small molecule inhibitor><small molecule therapeutics><topical microbicide><translation><vaccine development><virus envelope><virus genome><virus protein>