Hybrid Methods for Prediction and Design of Novel Human Influenza Antibodies

新型人类流感抗体预测和设计的混合方法

• 批准号: 8919482
• 负责人: James E Crowe
• 金额: $ 43.33万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-05 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8919482
• 关键词: Affinity; Antibodies; Antibody Affinity; Antigens; Binding; Birds; California; Collection; Complex; Computational Biology; Computer Simulation; Computing Methodologies; Coupled; Data; Deuterium; Development; Disease; Disease Outbreaks; Electron Microscopy; Exhibits; Ferrets; Future; H5 hemagglutinin; Head; Health; Hemagglutinin; Human; Hybridomas; Hybrids; Immune; Immunology; Infection; Influenza; Influenza A Virus, H5N1 Subtype; Influenza Therapeutic; Lead; Mass Spectrum Analysis; Methods; Modeling; Mutation; Nature; Point Mutation; Proteins; Research; Research Institute; Resolution; Specificity; Structure; Surface; Testing; Therapeutic antibodies; Universities; Vaccinated; Vaccines; Validation; Virus; X-Ray Crystallography; base; design; improved; influenzavirus; multidisciplinary; mutant; neutralizing antibody; neutralizing monoclonal antibodies; novel; pandemic disease; particle; receptor binding; research study; respiratory; response; screening; sialic acid receptor; stem; structural biology; transmission process; ward

The present proposal “Hybrid Methods for Prediction and Design of Novel Human Influenza Antibodies” will identify and develop novel influenza antibodies. There are three types of influenza viruses known, of which influenza type A is further differentiated into 2 groups, 17 subtypes based on the hemagglutinin (HA). Influenza A subtype H1 and H3 viruses seasonally infect humans. Several high-resolution structures of antibodies engaging influenza A HA have been determined by X-ray crystallography. Antibodies that engage the antigenically diverse head region of the trimeric HA molecules are most often narrow in breadth. Recently, two types of antibodies have been described that exhibit broad neutralization multiple subtypes of influenza. These two types of antibodies bind the more conserved stem region of HA or the conserved sialic acid receptor binding pocket within the head region. H5N1 influenza viruses traditionally infect birds, but have been responsible for several recent outbreaks limited to bird-to-human transmission. Recent research described adaptations of influenza H5N1 that confer respiratory droplet transmissibility from ferret to ferret, which may mimic the future development of a highly pathogenic pandemic human H5 virus in nature. It is poorly understood how humans vaccinated with conventional H5 immunogens might be protected from infection or disease with such mutants, which possess a limited number of surface point mutations in the HA. We present preliminary data on the isolation of human neutralizing monoclonal antibodies to the H5 head domain that recognize both wild-type and respiratory droplet transmissible H5 HAs from humans vaccinated with conventional H5 HA protein vaccine. The first objective of this proposal is to establish a pipeline ‘RAPID’ to rapidly identify and characterize human antibodies that broadly neutralize influenza viruses – an important strategy for the swift response to emerging threats to human health. We recently demonstrated that a new computational method termed “multi-state design” can recapitulate antibody maturation in silico, i.e., predicts mutations that increase antibody affinity to its target, and also predict antibody sequences encoding antibody proteins that are capable of broadly recognizing multiple target proteins. The second objective of this proposal is to design and test RAPID for (a) in silico maturation of head-binding antibodies to increase affinity for the HA antigen and (b) multi-state design to create stem-binding antibodies that recognize HAs of multiple different clades, groups, or even types.

目前的提案“预测和设计新型人类流感抗体的混合方法”

项目成果

Sampling alternative conformational states of transporters and receptors with AlphaFold2.

• DOI: 10.7554/elife.75751
• 发表时间: 2022-03-03
• 期刊: ELIFE
• 影响因子: 7.7
• 作者: del Alamo, Diego;Sala, Davide;Mchaourab, Hassane S.;Meiler, Jens
• 通讯作者: Meiler, Jens

Ligand-binding and -scavenging of the chemerin receptor GPR1.

• DOI: 10.1007/s00018-021-03894-8
• 发表时间: 2021-09
• 期刊: Cellular and molecular life sciences : CMLS
• 作者: Fischer TF;Czerniak AS;Weiß T;Schoeder CT;Wolf P;Seitz O;Meiler J;Beck-Sickinger AG
• 通讯作者: Beck-Sickinger AG

Introduction to the BioChemical Library (BCL): An Application-Based Open-Source Toolkit for Integrated Cheminformatics and Machine Learning in Computer-Aided Drug Discovery.

• DOI: 10.3389/fphar.2022.833099
• 发表时间: 2022
• 期刊: Frontiers in pharmacology
• 影响因子: 5.6
• 作者: Brown BP;Vu O;Geanes AR;Kothiwale S;Butkiewicz M;Lowe EW Jr;Mueller R;Pape R;Mendenhall J;Meiler J
• 通讯作者: Meiler J