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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.

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.

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.

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.

Cyclic Peptide Inhibitors of The SARS-Cov-2 Main Protease

The SARS-CoV-2 virus has rapidly spread across the globe with severe medical, social, and economic costs. The Researchers at the University of California Irvine have designed novel cyclic peptide inhibitors based on a crystal structure of an inactive variant of SARS-CoV, known as Mpro318. Based on a small library of cyclic peptide inhibitors, some candidates showed promising in vitro activity at low micromolar concentrations.

Lys-Covalent Pan-Inhibitors of Apoptosis Proteins (IAP) as Innovative Cancer Therapeutics

Prof. Maurizio Pellecchia and his colleagues at the University of California, Riverside (UCR) have developed novel Lys-covalent IAP inhibitors (Fig. 1) with low nanomolar activity and favorable PK (Fig. 2). When compared to Debio1143 (aka AT-406) and LCL 161, the UCR compounds have improved activity being irreversible.  Recently, new irreversible therapeutics in oncology have been developed as potential therapies for a variety of cancer. These irreversible agents present improved pharmacodynamics/ pharmacokinetics (PD/PK) properties over reversible agents, but their design is limited to targets that present a Cys residue within their binding site. UCR deployed a technology consisting of introducing a stable aryl-fluorosulfate electrophile that selectively interacts with Lys residues. UCR Compound 1 (Fig 1) is a potent, pan-IAP, Lys-covalent agent with favorable cell permeability and PK properties and that is likely superior to Debio1143 and LCL161 (Fig. 3). Fig. 1 Chemical composition and covalent docking of compound 1 in the binding pocket of the BIR3 domain of XIAP. Fig. 2 PK studies in mice with compound 1. Fig. 3 TNF sensitization of resistant melanoma cells by AT-406 (aka Debio 1143), LCL161 and the UCR compounds.  

Co-Administration Therapy to Prevent Neurodegeneration and Enhance Neuroprotection

Neurodegenerative diseases are a broad category of illnesses expected to affect 1 in 4 Americans. As they have a variety of underlying mechanisms and pathologies, there are currently no effective methods to prevent or modify disease progression. UCI researchers have developed a potential treatment utilizing a novel combination of two compounds for the abatement of brain inflammation and degeneration.

Novel Prodrug For Anti-Cancer Therapeutic Applications

Inventors at UCI have developed a modified nutrient transporter inhibitor for use as a cancer therapeutic with minimal side effects.

Novel Mixtures For Synergistic Activation Of M-Channels

Epilepsy is a seizure causing neurological disorder that affects over 50 million people, and it is estimated that half are ineffectively treated with current therapeutic options. Researchers at UCI have isolated components of a plant extract used to treat epilepsy in Africa and discovered that, when combined with an existing epilepsy medication, the mixture greatly decreases epileptic episodes and significantly increases survival rates in rodent models of epilepsy.

Steroid Regulation Of Inwardly Rectifying K+ Channel As Therapeutics Tool

UC Berkeley researches have discovered a new physiological modality of a potassium channel that is linked to the process of fluid regulation in the brain and is expressed in the choroid plexus (CP) and retinal pigment epithelia. CP is the main producer of cerebrospinal fluid that serves as a buffer to protect the brain, provides it with nutrients and removes waste products. The researchers have shown that application of progesterone resulted in strong potentiation of the inwardly rectifying potassium channel. The potentiation was progesterone-specific and independent of other known membrane progesterone receptors expressed in CP. 

Metal‐Binding Pharmacophore Library Yields the Discovery of a Glyoxalase 1 Inhibitor for Potential Treatment of Depression and Related Psychiatric Illnesses.

Anxiety and depression are the two most common psychiatric disorders in the U.S. and affect approximately one-in-five adults at some point in their lifetime. Depression is the leading cause of worldwide disability; anxiety disorders are highly comorbid with depression. Presently, there are several drugs approved by the U.S. Food and Drug Administration for the treatment of both anxiety and depression; however, these drugs have several important limitations. Antidepressant drugs are not effective in all patients, take weeks to produce therapeutic effects, and produce side effects that limit their use. Anxiolytic drugs produce sedating side effects and have significant abuse liability. Therefore, there is an urgent need for better therapeutic agents. Recent studies using both genetic and pharmacological techniques have implicated GLO1 in numerous behaviors, including several that are relevant to depression and anxiety.

Fragment-Based Stabilization Of 14-3-3/Client Protein-Protein Interactions

UCSF and Technical University of Eindhoven investigators have identified molecular fragments that stabilize 14-3-3/phospho-peptide and 14-3-3/phospho-protein interactions.  Further structure-guided and empirical medicinal chemistry will lead to a drug lead for the most advanced target (estrogen receptor).   

Hv1 Modulators and Uses

Researchers at UCI have engineered a class of Hv1 polypeptide modulators that selectively modulate Hv1 voltage gated channels while leaving other voltage gated channels unaffected. With no Hv1 modulators currently on the market, this class of Hv1 polypeptide modulators could provide solutions in birth control, autoimmune therapies, and tumor reduction.

Nell-1 As An Anti-Osteoinflammatory, Disease-Modifying Anti-Arthritis Agent

UCLA researchers in the Department of Plastic Surgery and the School of Dentistry have developed a novel anti-osteoinflammatory agent for the prevention and suppression of arthritis disease progression.

A New Approach To Treat/Manage Inflammatory Bowel Disease

Researchers at UCI have developed a safe, inexpensive drug for the treatment of inflammatory bowel diseases.

Drug Repurposing To Explore Novel Treatment For Cushing Disease

UCLA researchers in the Department of Medicine and the Department of Molecular and Medicinal Pharmacology have identified several small molecule reagents to treat Cushing disease.

Treatment Of Lysosomal Storage Disorders

UCLA researchers in the Departments of Neurology have developed a novel treatment for Lysosomal-storage diseases (LSDs) with neurological impairment.

Identification And Development Of Dual nSMase2-AChE Inhibitors For Neurodegenerative Disorders

UCLA researchers in the Department of Neurology, and the Department of Chemistry & Biochemistry have developed small molecule inhibitors of both the neutral sphingomyelinase 2 (nSMase2) and acetylcholinesterase (AChE) as novel therapeutics for neurodegenerative disorders caused by protein aggregation.

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.

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