A5059743839- SARS-CoV-2 and COVID-19 Research
- Viral gastroenteritis research and epidemiology
- HIV Research and Treatment
- Protein Structure and Dynamics
- RNA and protein synthesis mechanisms
- Enzyme Structure and Function
- RNA Interference and Gene Delivery
- Viral Infections and Immunology Research
- Bacteriophages and microbial interactions
- Monoclonal and Polyclonal Antibodies Research
- Animal Virus Infections Studies
- Glycosylation and Glycoproteins Research
- RNA modifications and cancer
- Viral Infections and Outbreaks Research
- Immune Cell Function and Interaction
- Bioinformatics and Genomic Networks
- RNA Research and Splicing
- Virology and Viral Diseases
- Virus-based gene therapy research
- Proteins in Food Systems
- RNA regulation and disease
- Escherichia coli research studies
- Bacterial Infections and Vaccines
- NF-κB Signaling Pathways
- Lipid Membrane Structure and Behavior
Moderna Therapeutics (United States)
2019-2025
Dimagi (United States)
2023
Yale University
2010-2013
University of California, San Francisco
2005-2012
Joint BioEnergy Institute
2010
QB3
2005-2008
University of Pittsburgh
2002
Infection with chikungunya virus (CHIKV) causes an acute illness characterized by fever, rash, and arthralgia. However, CHIKV infection can sometimes progress to chronic arthritis or even lethal disease. continues cause substantial morbidity worldwide as its vector mosquitoes expand spread. There are currently no approved vaccines antiviral drugs available for the prevention treatment of CHIKV. Although antibody therapy has shown promise in disease preclinical models, challenges remain...
The liver is an important site of host-microbe interaction. Although hepatocytes have been reported to be responsive lipopolysaccharide (LPS), the global gene expression changes by LPS and mechanism(s) which stimulates cultured remain uncertain. Cultures primary mouse were incubated with assess its effects on expression, hepatic transcription factors, mitogen-activated protein (MAP) kinase activation. DNA microarray analysis indicated that modulates selective more than 80 genes expressed...
Summary A SARS-CoV-2 vaccine is needed to control the global COVID-19 public health crisis. Atomic-level structures directed application of prefusion-stabilizing mutations that improved expression and immunogenicity betacoronavirus spike proteins. Using this established immunogen design, release sequences triggered immediate rapid manufacturing an mRNA expressing prefusion-stabilized trimer (mRNA-1273). Here, we show mRNA-1273 induces both potent neutralizing antibody CD8 T cell responses...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of a global pandemic. Safe and effective COVID-19 vaccines are now available, including mRNA-1273, which has shown 94% efficacy in prevention symptomatic disease. However, emergence SARS-CoV-2 variants led to concerns viral escape from vaccine-induced immunity. Several have decreased susceptibility neutralization by immunity, most notably B.1.351 (Beta), although overall impact on vaccine remains be...
Abstract Lipid nanoparticles (LNPs) are capable of delivering messenger ribonucleic acid (mRNA) efficiently and systemically as a result both particle composition architecture. The architecture is determined by how the various components interact with one another to establish stable equilibrium through self‐assembly. Coulombic attraction between anionic oligonucleotide cargo ionizable amino lipid within encapsulation media contributes coalescence particles, but other interactions also...
The RosettaBackrub server (http://kortemmelab.ucsf.edu/backrub) implements the Backrub method, derived from observations of alternative conformations in high-resolution protein crystal structures, for flexible backbone modeling. modeling is applied to three related applications using Rosetta program structure prediction and design: (I) structures point mutations, (II) generating conformational ensembles designing sequences consistent with these (III) predicting tolerated at protein–protein...
Interactions in protein networks may place constraints on interface sequences to maintain correct and avoid unwanted interactions. Here we describe a "multi-constraint" design protocol predict optimized for multiple criteria, such as maintaining sets of interactions, apply it characterize the mechanism extent which 20 multi-specific proteins are constrained by binding partners. We find that is accommodated at least two distinct patterns. In simplest case, all partners share key either single...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of a global pandemic. Safe and effective COVID-19 vaccines are now available, including mRNA-1273, which has shown 94% efficacy in prevention symptomatic disease. However, emergence SARS-CoV-2 variants led to concerns viral escape from vaccine-induced immunity. Several have decreased susceptibility neutralization by immunity, most notably B.1.351 (Beta), although overall impact on vaccine remains be...
Nipah virus (NiV) represents a significant pandemic threat with zoonotic transmission from bats-to-humans almost annual regional outbreaks characterized by documented human-to-human and high fatality rates. Currently, no vaccine against NiV has been approved. Structure-based design protein engineering principles were applied to stabilize the fusion (F) in its prefusion trimeric conformation (pre-F) improve expression increase immunogenicity. We covalently linked stabilized pre-F through...
Colonization of the gut and airways by pathogenic bacteria can lead to local tissue destruction life-threatening systemic infections, especially in immunologically compromised individuals. Here, we describe an mRNA-based platform enabling delivery pathogen-specific immunoglobulin A (IgA) monoclonal antibodies into mucosal secretions. The consists synthetic mRNA encoding IgA heavy, light, joining (J) chains, packaged lipid nanoparticles (LNPs) that express glycosylated, dimeric with...
Messenger RNA (mRNA) has emerged as a highly effective and versatile platform for vaccine delivery. We previously designed virus-like particle (VLP)-forming env-gag mRNA against human immunodeficiency virus-1 (HIV-1) that elicited envelope-specific neutralizing antibodies protection from heterologous simian-human virus (SHIV) infection in rhesus macaques. Here, we introduce key technological advance to this by inclusion of encoding retroviral protease process Gag produce mature VLPs....
The discovery that RNA molecules can fold into complex structures and carry out diverse cellular roles has led to interest in developing tools for modeling tertiary structure. While significant progress been made establishing the backbone is rotameric, few libraries of discrete conformations specifically use have validated. Here, we present six based on a simplified pseudo-torsional notation backbone, comparable phi psi protein backbone. We evaluate ability each library represent single...
Abstract Unlike proteins, the RNA backbone has numerous degrees of freedom (eight, if one counts sugar pucker), making modeling, structure building and prediction a multidimensional problem exceptionally high complexity. And yet tertiary structures are not infinite in their structural morphology; rather, they built from limited set discrete units. In order to reduce dimensionality physically reasonable way, shorthand notation was created that reduced torsion angles two (η θ, analogous φ ψ...
Vaccines have played a fundamental role in the control of infectious diseases. We previously developed messenger RNA (mRNA) vaccine against HIV-1 that forms virus-like particles (VLPs) through coexpression viral envelope with Gag. Here, we applied same principle to design VLP-forming mRNA severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To promote cognate interaction simian immunodeficiency virus (SIV) Gag, engineered different chimeric proteins encompassing ectodomain and...
Predicting which mutations proteins tolerate while maintaining their structure and function has important applications for modeling fundamental properties of evolution; it also drives progress in protein design. Here we develop a computational model to predict the tolerated sequence space HIV-1 protease reachable by single mutations. We assess comparison observed variability more than 50,000 sequences, one most comprehensive datasets on space. then extend second protein, reverse...
Monoclonal antibodies have been used successfully as recombinant protein therapy; however, for HIV, multiple broadly neutralizing may be necessary. We the mRNA-LNP platform in vivo co-expression of 3 antibodies, PGDM1400, PGT121, and N6, directed against HIV-1 envelope protein. mRNA-encoded were engineered single-chain Fc (scFv-Fc) to overcome heavy- light-chain mismatch. In vitro neutralization breadth potency constructs compared their parental IgG form. assessed ability these scFv-Fcs...
Abstract Monoclonal antibody (mAb) therapy is a promising infectious disease intervention strategy but limited to IgG1 isotypes that have restricted access mucosal sites. IgA well-established as the predominant isotype in secretions clinically underutilized. To enable development of IgA-based mAbs, we exploited mRNA platform technology and demonstrated expression functional, antigen-specific (IgA ) can limit bacterial invasion intestine prevent colonization lung. Moreover, vivo had enhanced...
<title>Abstract</title> Respiratory syncytial virus (RSV) is a significant cause of lower respiratory tract disease in young children and older adults. We designed codon optimized mRNA vaccine, mRNA-1345, that encodes the RSV F-glycoprotein stabilized prefusion (preF) conformation with deletion at cytoplasmic tail. mRNA-1345 protein expression was higher vitro versus previous mRNA-based vaccine candidates evaluated clinically. In rodent models, induced robust neutralizing preF-biased...