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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.

Modulating MD-2-Integrin Interaction for Sepsis Treatment

Researchers at the University of California, Davis have developed a potential therapeutic treatment for sepsis by modulating the interaction between integrins and Myeloid Differentiation factor 2 (MD-2).

Biosensor - Comprised of “Turn-on” Probes - with the Ability to Detect DNA Sequences in Living Cells

Researchers have developed a split-enzyme system that can detect genetic information in living cells by using luciferase linked to programmable DNA-binding domains.

Deep Learning-Based Approach to Accelerate T cell Receptor Design

Researchers at the University of California, Davis have developed a deep learning simulation model to predict mutated T-cell receptor affinity and avidity for immunotherapy applications.

Peptide Inhibitors of Human Voltage Gated Proton Channel hHv1 Activity to Reduce Inflammation

Human voltage-gated proton channels (hHv1) are implicated in a wide range of biological responses, including capacitation of sperm and stimulation of the innate immune response. Human sperm undergo a process called capacitation in the female reproductive tract, whereby intracellular pH rises and stimulates a progesterone-induced Ca2+ influx.  Researchers at the University of California, Irvine have discovered that this calcium influx is controlled by albumin activation of Hv1 voltage-gated proton channels.  Albumin activation of hHV1 in neutrophils also supports production and release of reactive oxygen species and protease during the immune respiratory burst.  These findings demonstrating a stimulatory role of albumin in both sperm and neutrophils has led to new therapeutic approaches to fertility and the treatment of inflammatory diseases.

Positive Allosteric Modulators Target TRPV1 with Analgesic Effects

Researchers at the University of California, Davis have developed de novo positive allosteric modulators (PAMs) that bind to TRPV1 proteins involved with pain-sensing in order to provide analgesic effects.

(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. 

Novel Agonist alpha2aAR Analgesics

Brief description not available

Kaposi Sarcoma Associated Herpesvirus Gene Function and Methods for Developing Antivirals, Anti-KSHV Vaccines, and KSHV Based Vectors

The inventors present a novel strategy for achieving pathogen opportunistic pathogenesis, with broad implications for treating infectious diseases. In a comprehensive analysis of Kaposi sarcoma associated herpesvirus (KSHV), a medically important virus, the inventors discovered novel antiviral targets and gene function, and identified opportunistic factors with dual functions of regulating both the immune environment/responses and viral reactivation/replication. This discovery includes:A collection of KSHV mutants with inactivation or deletion of each of the 91 predicted open reading frames (91 mutant strains). Methods and reagents (e.g. primers) for construction of the collection of KSHV mutants. The identity of 44 KSHV essential genes, which represent potential antiviral targets (including 27 newly identified essential genes). Methods for construction of gene-inactivation and rescued mutants, and for tagging and introducing foreign genes into the KSHV genome. These approaches can be used for vector and vaccine development. Growth properties of viral mutants with inactivation of non-essential genes.Methods for screening mutants in different human cell lines.Opportunistic factors of KSHV and all other animal viruses that have dual functions as both the modulators of immune environment/response and regulators of viral reactivation/replication.   

Reinforcement Learning with Real-time Docking of 3D Structures for SARS-COV-2

The inventors propose a novel framework generating new molecules that potentially inhibit the Mpro protein, the main protease of SARS-COV-2. The technology combines deep reinforcement learning (RL) with real-time molecular docking on the 3d structure of Mpro using AutoDock Vina, an open-source program for doing molecular docking. A second second docking software, Glide, was used to validate the generated molecules. The AutoDock and Glide docking softwares showed consensus on 41 molecules as potential potent Mpro inhibitors that were sufficiently easy to synthesize. The inventors show that this method samples the drug chemical space efficiently, covering a much broader space than molecules submitted to the COVID moonshot project, and the molecules have the correct shape and non-bonded interactions to fit into the binding pocket. Moreover, this approach only relies on the structure of the target protein, which means it can be easily adapted for future development of other inhibitors.

Humanized, potent monoclonal antibodies against murine and human integrin avb8 for cancer immunotherapy and prevention of corneal scarring after cataract surgery

Immunotherapy has revolutionized the treatment of many cancers, but even for the most sensitive tumor types most patients do not respond to current immunotherapy regimens. One major block to effective anti-tumor immunity is inhibition of the function of effector T cells by active TGFβ in tumors. For this reason, several major pharmaceutical companies have invested substantial resources in developing inhibitors of TGFβ ligands or TGFβ signaling to enhance anti-tumor immunity. However, because TGFβ isoforms (TGFβ1, 2 and 3) play multiple important homeostatic roles, highly effective inhibition of TGFβ function causes severe toxicity, as seen by the embryonic or perinatal lethality of knockout of each of the 3 mammalian TGFβs. Even the relatively ineffective TGFβ inhibitors that have entered clinical trials have been withdrawn because of unacceptable toxicity (cardiac valve thickening and skin cancer). We have thus spent the past 20 years developing drugs targeting TGFβ activating integrins, which only activate a small fraction of extracellular latent TGFβ in precise contexts relevant to specific diseases, with the goal of increasing precision and greatly reducing the potential for toxicity. 

Conjugates That Combine HDAC Inhibitors and Retinoids into Disease Preventatives/Treatments

Researchers at the University of California, Davis have developed methods for creating compositions with the potential to prevent or treat cancer or metabolic diseases. These compositions combine conjugates with covalently linked HDAC inhibitors and retinoids.

Laser Photocoagulation To Stabilize Collector Channels To Enhance Aqueous Flows

Inventors at the University of California, Irvine have developed a laser-emitting device that treats glaucoma by enlarging and stabilizing collector channels in order to enhance aqueous outflow and reduce intraocular pressure (IOP).

Acid Degradable Solid Lipid Nanoparticles

The inventors demonstrate that polyethylene glycol (PEG) conjugated to cholesterol via an acid degradable linkage composed of an azide-benzaldehyde acetal has the potential to allow solid lipid nanoparticles (SLNs) to be PEGylated with mole ratios up to 50%. The azide-benzaldehyde acetal, has its azide in the para position, and generates stable acetals with a t ½ of > 1000 minutes at pH 7.4. These PEG-acetals can be formulated into SLNs, and stored, and then reduced prior to biological use, to generate an amino acetal that has t ½ < 60 minutes at pH 7.4 and several minutes at pH 5.0. The ultra-PEGylated lipids were efficient at transfecting a variety of organs, including the muscle, the lung, spleen and liver and were also able to transfect the blood. Acid degradable PEG-lipids have great potential for overcoming the PEG dilemma, but have previously been challenging to develop due to the synthetic challenges associated with working with acetals and their instability at pH 7.4. (SLNs contain a PEGylated lipid, generally in the 1-5% range, which is needed to maintain SLN stability, size, and tissue diffusion, and lower toxicity. However, excessive PEGylation also results in lower cell uptake and endosomal disruption — a paradox referred to as the PEG dilemma.) The inventors anticipate numerous applications of the azide-benzaldehyde acetal linker, given its unique ability to be stable prior to reductive activation. 

Sialic Acid Inhibitor in Cancer Treatment and Immunotherapy

Researchers at the University of California, Davis have developed a method of inhibiting sialic acid expression which is commonly related to bacterial and viral infections, metastatic cancer, and other pathogenic processes.

(SD2021-146) ANTICANCER AND ANTIFUNGAL SPLICE MODULATORS

While splice modulators have entered clinical trials, limited clinical efficacy in splicing factor mutation-driven malignancies, such as acute myeloid leukemia, has remained a challenge. There is a pressing unmet medical need for developing potent small molecule splice modulators for the treatment of a broad array of malignancies characterized by splicing deregulation.  However, the inability to practically access gram-scale lead molecules with viable pharmacological properties continues to hinder their application.

(SD2020-497) Light-activated tetrazines enable live-cell spatiotemporal control of bioorthogonal reactions

Bioorthogonal ligations encompass coupling chemistries that have considerable utility in living systems. Among the numerous bioorthogonal chemistries described to date, cycloaddition reactions between tetrazines and strained dienophiles are widely used in proteome, lipid, and glycan labeling due to their extremely rapid kinetics. In addition, a variety of functional groups can be released after the cycloaddition reaction, and drug delivery triggered by in vivo tetrazine ligation is in human phase I clinical trials. While applications of tetrazine ligations are growing in academia and industry, it has so far not been possible to control this chemistry to achieve the high degrees of spatial and temporal precision necessary for modifying mammalian cells with single-cell resolution.

Multiplex Epigenetic Editing using a Split-dCas9 System

Researchers at the University of California, Davis have developed a new epigenetic editing system that overcomes packaging limitations of viral delivery systems and can be used for multiplexed epigenetic editing of a genome.

Control Of Chimeric Antigen Receptor Activation By Their Hinge And Transmembrane Domains

UCSF inventors have created a hybrid sequence that, when engineered into Chimeric Antigen Receptor (CAR) T cells, promotes activation of the cells solely with CD28 antibodies or CD28 ligands. The sequence is a combination of the CD28 or IgG4 hinge region and the CD28 transmembrane, and represent a new opportunity to control T cell function. The technology has been tested in vitro with in vivo studies ongoing. The added functionality through this sequence has potential to promote survival and homeostasis of CAR T cells in the absence of CAR target and improve the specificity and toxicity profiles of current CAR T therapies. 

Novel Estrogen Receptor ß (ERß) Drugs for the Treatment of Multiple Sclerosis (MS)

Prof. Seema K. Tiwari-Woodruff from the University of California, Riverside, Prof. John Katzellenbogen and colleagues from the University of Illinois have developed novel estrogen receptor β (ERβ) drugs for the treatment of MS. These novel MS drugs are specific for ERβ and have tremendous potential for the treatment of MS as well as other neurodegenerative diseases. In general, estrogens have anti-inflammatory and neuroprotective activities and clinically reduce the severity of MS and other neurodegenerative diseases. The compounds are more superior to other estrogenic drugs due to their specificity for ERβ and lack of undesirable effects such as feminization and increased risk of cancer. Fig 1: Therapeutic treatment with the UCR ERβ ligands began at peak disease (day 17) and was continued daily till day 36. ERβ ligands (blue, and orange) significantly attenuated clinical disease severity compared to vehicle treatment (red).  

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