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Compositions and Methods for Treating Viral Infections

Researchers at the University of California, Davis (“UC Davis”) have developed methods for screening and targeting regions of viral genomes to identify drugs that inhibit the replication of RNA viruses.

(SD2022-010) Method for transmembrane protein semisynthesis and reconstitution in lipid membranes

Cellular lipid membranes are embedded with transmembrane proteins crucial to cell function. Elucidating membrane proteins’ diverse structures and biophysical mechanisms is increasingly necessary due to their growing prevalence as a therapeutic target and sheer ubiquity in cells. Most biophysical characterization strategies of transmembrane proteins rely on the tedious overexpression and isolation of recombinant proteins and their reconstitution in model phospholipid bilayers.Unfortunately, membrane protein reconstitution depends on the use of denaturing and unnatural detergents that can interfere with protein structure and function. We have developed a detergent‐free method to reconstitute transmembrane proteins in model phospholipid vesicles and GUVs. Additionally, transmembrane proteins are difficult to express in cells due to the extreme insolubility of their transmembrane domain. By incorporating a synthetic transmembrane peptide into liposomes and simply expressing soluble portions of transmembrane proteins in cells, we can use this semisynthetic ligation strategy to more easily construct functional transmembrane proteins and reconstitute them into liposomes for biophysical and biochemical studies.Inteins can be found contiguously or non contiguously within some proteins. Non‐contiguous inteins are called “split inteins”. Inteins can be thought of as a type of protein intron which splices itself out of proteins. When non‐contiguous inteins find and bind to each other, they are then able to excise themselves resulting in the ligation of their respective exteins. Split intein pairs (C‐intein and N‐intein) can be attached to proteins of interest in synthetic and cellular systems to ligate protein sequences together.

Anti-Influenza Small Molecule Therapy

Professor Jiayu Liao from the University of California, Riverside has identified small molecules that block  the Influenza B virus (IBV) from replicating by inhibiting the SUMOylation pathway. This IBV virus replication inhibition works by using the novel SUMOylation inhibitor, STE025, to inhibit the SUMOylation of the IBV M1 protein. SUMOylation also has active roles in the pathogenesis of several diseases, such as tumorigenesis, neurodegenerative diseases and infections, and as such, this technology could potentially be applied to these types of diseases as well. Fig 1: Cell death induced by IBV infection can be rescued by the UCR SUMOylation-specific inhibitor, STE025 (blue) compared to cells not exposed to IBV (green), and cells exposed to IBV without the UCR inhibitor (purple and red).  

PHAGE-MEDIATED DELIVERY OF GENES TO GUT MICROBIOME

Researchers at UCSF have developed methods to engineer bacteriophage for gene delivery to gut microbiome. 

ENGINEERED ACE2 RECEPTOR TRAPS TO BLOCK SARS-COV-2 INFECTION

Researchers at UCSF and the Chan Zuckerberg Biohub have developed a set of ACE2 variants which potently block SAR-CoV-2 infection in cells. 

Eradication Of Human Cancer Cells By Antigen Specific Delivery Of Carbon Monxide With A Family Photoactivatable Antibobody Photocorm Conjugates

PhotoCORMs are compounds that release Carbon monoxide (CO) upon exposure to light. CO released from photoCORMs exposed to light is known to cause apoptotic cell death and can sensitize human cancer cells to chemotherapeutics. Drug resistance is often encountered in cancer chemotherapy. In addition, efforts to minimize toxicity from chemotherapy have met with little success. A UC Santa Cruz researcher has developed a system to specifically deliver photoCORMs to tumors and presensitize those tumors to conventional chemotherapy

Gene Editing in Utero via Non-Viral, Lipid Nanoparticle Delivery of mRNA Complexes

Researchers at the University of California, Davis have developed a new method of in utero gene editing through lipid nanoparticle delivery of mRNA gene editors.

Sequential Targeting and Crosslinking Nanoparticles for Tackling the Multiple Barriers to Treat Brain Tumors

Researchers at the University of California, Davis have developed an approach to improve drug delivery to tumors and metastases in the brain. Their multi-barrier tackling delivery strategy has worked to efficiently impact brain tumor management while also achieving increased survival times in anti-cancer efficacy.

Water-Soluble Iron-Porphyrin Complexes Capable Of Acting As Antidotes For Carbon Monoxide Poisoning

CO poisoning is the most common form of poisoning worldwide. In the United States alone, over 50,000 emergency department visits each year are attributed to CO exposure. Despite the prevalence of CO poisoning, there is no clinically-approved antidote available.Current best practices involve placing the afflicted subject in fresh air, delivering 100% O2, or administering superatmospheric levels of O2 in a hyperbaric chamber. These treatments all serve to clear CO from the body by displacing it from metalloproteins with O2. The typical half-life of COHb in the bloodstream is 5.3 h, but hyperbaric O2 (1.5-3 atm) can decrease this half-life to < 1 h.Unfortunately, these large chambers are generally located in tertiary care centers to which patients must be transported. Moreover, hospitals typically house only a few such chambers, which would be rapidly overwhelmed in the event of a mass exposure.Although there are no clinically approved antidotes to CO poisoning, two strategies have been described: the creation of molecules that enhance the rate of release of CO from carboxyhemoglobin (formed during CO poisoning) and the creation of molecules that bind CO more strongly than physiologically important proteins such as hemoglobin.  

Improving primary human NK cell expansion with a chimeric cytokine receptor

Natural Killer (NK) cells are innate lymphocytes with the ability to lyse tumor cells. One limitation of NK cells when encountering tumor cells is that they can’t control their own proliferation and expansion to increase their numbers at the tumor site. Current approaches to increase NK cell numbers and stimulate NK-cell anti-cancer functions include systemic administration of recombinant cytokines (IL-15, IL-2, or IL-12) that exhibit systemic or local toxicity or constitutive expression of IL-15 in transduced NK cells. Researchers at UCSF have engineered NK cells with a chimeric cytokine receptor (CCR) that provides autocrine signaling through the secretion of IFNγ, which subsequently enhances NK cell proliferation and function to support NK cell anti-cancer immune response specifically at the tumor site while avoiding recombinant cytokine- related toxicity. 

Human Astrovirus Neutralizing Monoclonal Antibody Sequences

Human astroviruses cause viral gastroenteritis in children, elderly, and immune-compromised individuals. VA1 clade human astroviruses can cause encephalitis or meningitis in immune-compromised individuals. There are no preventative measures or antiviral therapies for human astrovirus disease.

Antidotes to Cyanide Poisoning (Use Of Cisplatin Analogues)

See patent application publication no. US20200276148A1. The present application provides a compound for treatment and prevention of cyanide poisoning. 

Methods To Generate Novel Acyl-Trna Species

The inventors have discovered PylRS enzymes that accept -thio acids, N-formyl-L-amino acids, and diverse -carboxyl acid monomers (malonic acids) that are formally precursors to polyketide natural products. These monomers are all accommodated and accepted by the translation apparatus in vitro. High-resolution structural analysis of the complex between one such PylRS enzyme and a meta-substituted 2-benzylmalonate derivative reveals an active site that discriminates pro-chiral carboxylates and accommodates the large size and distinct electrostatics of an -carboxyl acid substituent.This discovery emphasizes the potential of PylRS for evolving new enzymes capable of encoding diverse non-L-amino acids in synergy with natural or evolved ribosomes. The absence of orthogonal aminoacyl-tRNA synthetase enzymes that accept non-L-amino acids is the primary bottleneck hindering the in vivo translation of sequence-defined hetero-oligomers. 

Leveraging microbiome bacteria, bacterial modulators, and novel microbial species for prevention, diagnosis, and treatment of inflammatory diseases, respiratory system infections, and premature birth

The following technologies encompass a portfolio of microbiome-centric inventions intended to address unmet diagnostic and treatment needs in the areas of inflammatory disease and respiratory system infections, including prevention in infants. 

Transformable Smart Peptides as Cancer Therapeutics

Researchers at the University of California, Davis have developed smart, supramolecular, materials that can assemble into nanoparticles. These particles can then be used to target tumor cells.

Integrin Binding to P-Selectin as a Treatment for Cancer and Inflammation

Researchers at the University of California, Davis have developed a potential drug target for cancer and inflammation by studying the binding of integrins to P-selectin.

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