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(2020-266) Protein Domains For Modulation Of Rna Stability And/Or Translation

Existing art in modulation of gene expression by nucleic acid targeting mechanisms primarily comprises methods for REDUCING gene expression, e.g. via DNA targeting (CRISPR gene knockout, reduction of transcription via CRISPR-i), or RNA targeting (shRNAs/siRNAs, ASOs, microRNA mimics). ENHANCEMENT of gene expression on the RNA level has been achieved using microRNA inhibitors; however the effects are typically small and are not target-specific (many other microRNA target-RNAs are also upregulated).The molecular functions of the majority of RNA-binding proteins (RBPs) remain unclear, highlighting a major bottleneck to a full understanding of gene expression regulation. 

2-D Polymer-Based Device for Serial X-Ray Crystallography

Researchers at the University of California, Davis have developed a single-use chip for the identification of protein crystals using X-ray based instruments.

One-Pot Multienzyme Synthesis of Sialidase Reagents, Probes and Inhibitors

Researchers at the University of California, Davis, have developed an environmentally friendly one-pot multienzyme (OPME) method for synthesizing sialidase reagents, probes, and inhibitors.

Improved guide RNA and Protein Design for CasX-based Gene Editing Platform

The inventors have developed two new CasX gene-editing platforms (DpbCasXv2 and PlmCasXv2) through rationale structural engineering of the CasX protein and gRNA, which yield improved in vitro and in vivo behaviors. These platforms dramatically increase DNA cleavage activity and can be used as the basis for further improving CasX tools.The RNA-guided CRISPR-associated (Cas) protein CasX has been reported as a fundamentally distinct, RNA-guided platform compared to Cas9 and Cpf1. Structural studies revealed structural differences within the nucleotide-binding loops of CasX, with a compact protein size less than 1,000 amino acids, and guide RNA (gRNA) scaffold stem. These structural differences affect the active ternary complex assembly, leading to different in vivo and in vitro behaviors of these two enzymes.

In plantae production of heterologous proteins using viral amplicons

Researchers at the University of California, Davis have developed a viral amplicon-based vector system for heterologous protein expression and production in plants.

A New Cell-free Protein Expression System with three-fold higher protein yield in batch and continuous mode than existing systems

Researchers at the University of California, Davis have developed a method for preparing a bacterial cell lysate that results in higher protein expression than existing cell-free systems. The new whole-cell lysate system comes with additional advantages, including the ability to synthesize protein from linear DNA, directly amenable to continuous or flow-based reaction, and compatibility with existing manufacturing workflow.

Site-Specific Coupling Of Biomolecules Using Orthoquinones And Thiols

The inventors have developed an enzymatically catalyzed method for simple and rapid coupling of biomolecules to native amino acids on protein surfaces. This method is capable of attaching tyrosine or phenol containing molecules, peptides, or proteins to cystine or thiol containing targets at neutral pH with high yields. The inventors demonstrate the utility of this system by modifying Cas9 and other proteins with fluorophores, peptides, and whole proteins, such as green fluorescent proteins (GFPs) and antibody short chain variable fragments. This technology represents a novel paradigm in biomolecule coupling.

Methods To Suppress Viral Infection Of Mammalian Cells

To meet the ever-growing demand for effective, safe, and affordable protein therapeutics, decades of intense efforts have aimed to maximize the quantity and quality of recombinant proteins produced in Chinese hamster ovary (CHO) cells. CHO cells are extensively used to produce biopharmaceuticals and one advantage is their reduced susceptibility to many human virus families. However, there have been a few episodes of animal viral contamination of biopharmaceutical production runs, mostly from trace levels of viruses in raw materials. These infections more often caused by RNA viruses have led to expensive decontamination efforts and threatened the supply of critical drugs. Viral contamination in biopharmaceutical manufacturing can lead to shortages in the supply of critical therapeutics. Therefore there is a need to understand the mechanisms by which CHO cells are infected and how the cells can be universally engineered to enhance their viral resistance.

Chemoselective Side-Chain Modifications Of Methionine-Containing Elastin-Like Polypeptides

UCLA researchers in the Department of Bioengineering and Department of Chemistry & Biochemistry have developed a novel method for the introduction of various functional groups onto recombinant elastin-like polypeptides (ELPs), creating new compositions of ELPs that may be used for medical therapeutic or diagnostic applications.

Protein Translation Machinery One Shot (TraMOS) Tool

Researchers at the University of California, Davis have developed a microbial culture capable of translating mRNA molecules into a polypeptide with a single reaction mixture.

Living Bioreactor for Stoichiometric Protein Production

Living bioreactors are powerful systems for producing a variety of valuable compounds. The versatility of such bioreactors is one of the more useful aspects of the system. Large quantities of compounds or cellular components can be produced efficiently, with minimal cost. Alternately, these systems can be used to produce pathway components that are necessary in the production of secondary products. A common problem with such systems is that they are limited by non-uniform production of pathway components, or require an isolation process to ensure the components are in the appropriate quantity and sequence in the process. Inventors at Texas A&M and UC San Francisco have developed a novel technique to address these issues. The technology effectively results in a stoichiometric production of protein components that are produced in an array, ready for secondary production.

Preparation Of Functional Homocysteine Residues In Polypeptides And Peptides

UCLA researchers in the Department of Bioengineering and Department of Chemistry & Biochemistry have developed a novel method for efficient, chemoselective transformation of methionines in peptides and polypeptides into stable, functional homocysteine derivatives. This method provides a means of creation of new functional biopolymers, site-specific peptide tagging, and synthesis of biomimetic and structural analogs of peptides.

In Situ Lipid Synthesis for Protein Reconstitution (INSYRT)

While current methods for membrane protein functional reconstitution in biomimetic membranes approaches are powerful and have uncovered fundamental properties of protein function, they are methodologically cumbersome, requiring chromatography steps to remove detergents. Moreover, structural features normally found in cell membranes such as curvature and polarity are mostly absent. In this regard, an efficient reconstitution methodology that better mimics the native chemical environment of a whole-cell embedded protein would be highly useful.

Use of Mutant Kv7.2 Channels for Anti-Epileptic and Pain Therapies

During seizures or pain-induced inflammation, excess chemical mediators suppress potassium channels mediating neuronal activity and thereby inactivate new generation anti-epileptic drugs and painkillers acting on those channels. The invention describes a gene therapy using a genetically-engineered potassium channel that reduces adverse effects by silencing neuronal hyperactivity while maintaining normal neuronal activity in the presence of chemical mediators to treat epilepsy and pain.

An Antibody to Phospho T3 of Human Huntingtin

Huntington’s disease (HD) is a neurodegenerative genetic disorder caused by abnormal function of mutated Huntingtin protein. The invention uncovers an antibody to a new post-translational modification site that affects human Huntingtin aggregation and pathogenesis of HD.

Improved Cell-Free Protein Synthesis For Protein Microarray

Researchers at UC Irvine have developed a cell-free (CF) protein synthesis system to solubilize and synthesize highly hydrophobic membrane proteins that would typically aggregate using current CF synthesis systems. With such high amounts of synthesized proteins, researchers intend to build protein microarrays for diagnostic purposes.

Therapeutic strategies for Huntington’s Disease using stop codon suppression

In Huntington’s Disease (HD), aberrant splicing of the huntingtin protein can produce a highly toxic peptide that accumulates in the brain. The invention describes methods to minimize the toxicity of spliced proteins.

Mammalian Cell Culture Optimization

Biotherapeutic proteins manufactured in cell culture systems have transformed modern medicine. Selling many tens of billions per year, new biotherapeutics such as monoclonal antibodies have delivered dramatic clinical results, while posing significant manufacturing problems.: During the cell culture manufacturing process, toxic bioproducts such as lactate and ammonia have posed considerable challenges in bioprocessing, since they limit cell growth and impact critical quality attributes of recombinant protein production (e.g., therapeutic drugs, enzymes). That is because the lactate alters the regulation of biosynthetic enzymes, and can lead to changes in pH in the culture. To mitigate the negative effects of lactic acid accumulation and control the culture pH, chemical ‘base’ is added to the media during the course of a bioprocess. However, the base addition negatively impacts the bioprocess by inhibiting growth and shortening the length of time in which the cells can produce the recombinant protein. This leads to reduced yield, and increased cost-of-goods. Thus, it is of great interest to eliminate lactate production, and UC San Diego researchers have recently developed a new process for achieving this.  

Dual Targeting Agents For Alzheimer's Disease

Alzheimer’s Disease is a prevalent neurodegenerative disorder affecting 10% of people over age 65. It is characterized by a progressive loss of cognitive function and memory impairments that are associated with increased peptide and protein aggregation in the brain. The invention herein describes a novel therapy for Alzheimer’s Disease which would promote the removal of toxic Amyloid-beta peptides out of the brain.

A Protein Domain That Protects Ubiquitinated Forms Of Proteins From Degradation In Cis And In Trans

Ubiquitylation affects proteins in many ways, such as activation or inactivation, and signaling for their degradation. It is not fully understood how ubiquitin effects all proteins or how researchers may use it to control cellular processes. This invention describes novel fusion proteins that protect ubiquitylated forms of the target proteins from degradation.

Pyrite Shrink-Wrap Laminate As A Hydroxyl Radical Generator

The invention is a diagnostic technology, as well as a research and development tool. It is a simple, easy to operate, and effective platform for the analysis of pharmaceuticals and biological species. Specifically, this platform generates hydroxyl radicals for oxidative footprinting – a technique commonly employed in protein mapping and analysis. The platform itself is inexpenisve to fabricate, scalable, and requires nothing more than an ordinary pipet to use. In addition, it is highly amenable to scale-up, multiplexing, and automation, and so it holds promise as a high-throughput method for mapping protein structure in support of product development, validation, and regulatory approval in the protein-based therapeutics industry.

A Method For Predicting Glycosylation On Secreted Proteins

Glycosylation is a key post-translational modification that can affect critical properties of proteins produced in biopharmaceutical manufacturing, such as stability, therapeutic efficacy, or immunogenicity. However, unlike a protein's amino acid sequence, glycosylation is hard to engineer since it does not follow any direct equivalent of a genetic code. Despite various attempts to computationally model the process of glycosylation, industrial glycoengineering is still largely carried out using costly and time-consuming trial-and-error strategies and could greatly benefit from computational models that would better meet the requirements for industrial utilization.

MMP-Selective Antibody Inhibitors

Prof. Xin Ge and his colleagues at the University of California, Riverside have developed a library of human, selective MMP-14 antibody inhibitors with nanomolar activities. Unlike known MMP inhibitors, n-TIMP-2 and GM6001, that inhibit a broad spectrum of the MMP family these antibody inhibitors do not exhibit off-target effects with other MMP family members such as MMP-2/MMP-9. Fig. 1 shows inhibition selectivity tests of Fab 3A2, GM6001 and n-TIMP-2. Unlike n-TIMP-2 and GM6001, Fab3A2 shows selectivity for MMP-14 and did not inhibit MMP-2 or MMP-9.     Fig. 2 shows the weight and number of the pulmonary metastic lesions in B16F1 (Mock) and B16F1 MT-MMP (mMT1) mouse models. The mMT1 mouse model treated with the 3A2 (mMT+3A2) antibody showed a reduction in the weight and number of pulmonary metastatic lesions.

Functional Illumination in Living Cells

Researchers at the University of California, Davis, have developed a novel method of developing a wide array of small functional illuminants that do not hinder cell function.

Reversible Chemoenzymatic Protein Labeling

Some of nature’s most complex molecules are made by cellular factories that rely on an acyl carrier protein (ACP) to shuttle growing molecules along biological assembly lines. Post-translational protein modification is important for adding functions to proteins that can be exploited for therapeutics, protein engineering, affinity design and enzyme immobilization, among other applications. Commercial techniques for attaching labels to acyl carrier protein (ACP) and other carrier proteins are currently in use.

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