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Design of Antivirals and Immunogens Targeting Paramyxoviruses

针对副粘病毒的抗病毒药物和免疫原的设计

基本信息

批准号：
10889846
负责人：
Eva-Maria Strauch
金额：
$ 37.56万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-16 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10889846
关键词：
Affinity Algorithms Amino Acid Sequence Antibiotics Antibody Response Antigens Antiviral Agents Avidity Back Bacterial Infections Binding Binding Proteins Binding Sites Biological Assay Biological Models Bronchiolitis Case Fatality Rates Cell membrane Cessation of life Chimeric Proteins DNA biosynthesis DNA sequencing Data Detection Development Diagnostic Disease Outbreaks Ebola Elements Emerging Communicable Diseases Encephalitis Epitopes Evaluation Family Family member Foundations Generations Glycoproteins Goals HIV HIV-1 Hendra Virus Henipavirus Immune Evasion Immune system Infant Infection Influenza Knowledge Libraries Mediating Membrane Membrane Fusion Membrane Glycoproteins Membrane Proteins Methodology Methods Modeling Molecular Molecular Conformation Monitor Nipah Virus Paramyxovirus Pathogenicity Pattern Pneumonia Preparation Prophylactic treatment Protein Engineering Proteins Protocols documentation Reagent Receptor Cell Resolution Respiratory syncytial virus Respiratory syncytial virus RSV F proteins Role Scaffolding Protein Severe Acute Respiratory Syndrome Site Structure Surface Vaccination Vaccine Design Vaccines Variant Viral Viral Proteins Virus Virus Diseases Work bioweapon computer design computer generated design genetic selection improved influenza virus strain influenzavirus inhibitor innovation insight large datasets member neutralizing antibody new epidemic next generation novel novel therapeutics receptor receptor binding response vaccine candidate

项目摘要

Abstract Viral infection results in thousands of deaths and an enormous humanitarian burden every year, yet unlike antibiotics for bacterial infection, very few antivirals are available. At present, few methods exist for generating effective antivirals. The increasing availability of atomic resolution structural information of various viral surface proteins promises to chance this. The overall objective of this application is to use the surface glycoproteins of Paramyxoviruses (PMV) as a model system to generate design methodologies that will take advantage of structural features present in a broad range of viruses, resulting in a robust platform for the design of new therapeutics, diagnostics and immunogens for vaccination. PMVs are an ideal model system as their family members have the same fold for receptor recognition yet bind to very different host cell receptors. We recently demonstrated that computational protein design can be used to generate de novo antivirals that broadly neutralize diverse strains of influenza. These computer-generated proteins can also function as highly sensitive diagnostics. Guided by these results, the following specific aims will be pursued: (i) Develop general design strategies to target virus:host cell receptor interactions and design antivirals using Hendra and Nipah Viruses as model systems; (ii) inhibit membrane fusion of RSV by targeting the intermediate fusion states; and (iii) selectively stabilize the pre- and post-fusion state stabilization of the F- protein of RSV and probe their contributions to infectivity and vaccine design. The first aim is based on the observation that many receptor-binding sites of enveloped viruses lay within a recessed pocket, enabling evasion from the immune system. Computational design strategies which specifically target pockets will enable the development a robust algorithm to generate antiviral proteins which bind at these sites. The second aim is based on the hypothesis that the post-fusion structure of viral surface proteins provides the blueprint to targeting their transition state. Small proteins will be designed to molecularly “jam” the 3-helical core structure that is common to most type I fusion proteins and therefore will be provide a general method to inhibit type I fusion proteins, which include viruses such as HIV-1, Ebola, SARS and others. Lastly, the objective of aim three is to simultaneously model the pre- and post-fusion states of the F-protein of RSV to generate variants to favor one state over the other. Variants will be assayed for changes in infectivity. The trapped pre-fusion state stabilized by disfavoring the post-fusion state will provide the basis for a new angle on immunogen design. If successful, data on designs will be fed back into the developed algorithm, leading to rapid development of new antivirals against emerging epidemics.

摘要

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

De novo design of picomolar SARS-CoV-2 miniprotein inhibitors.

皮摩尔SARS-COV-2小蛋白抑制剂的从头设计。

DOI：
10.1126/science.abd9909
发表时间：
2020-10-23
期刊：
Science (New York, N.Y.)
影响因子：
0
作者：
Cao L;Goreshnik I;Coventry B;Case JB;Miller L;Kozodoy L;Chen RE;Carter L;Walls AC;Park YJ;Strauch EM;Stewart L;Diamond MS;Veesler D;Baker D
通讯作者：
Baker D

Sampling of structure and sequence space of small protein folds.

DOI：
10.1038/s41467-022-34937-8
发表时间：
2022-11-22
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Linsky, Thomas W.;Noble, Kyle;Tobin, Autumn R.;Crow, Rachel;Carter, Lauren;Urbauer, Jeffrey L.;Baker, David;Strauch, Eva-Maria
通讯作者：
Strauch, Eva-Maria

Targeting Viral Surface Proteins through Structure-Based Design.