Stability issues in membrane-free coacervates have been addressed with coating strategies, but these approaches often compromise the permeability of the coacervate. Researchers from UC San Diego have invented a facile approach to maintain both stability and permeability using tannic acid and then demonstrate the value of this approach in enzyme-triggered drug release. First, the researchers developed size-tunable coacervates via self-assembly of heparin glycosaminoglycan with tyrosine and arginine-based peptides. A thrombin-recognition site within the peptide building block results in heparin release upon thrombin proteolysis. Notably, polyphenols are integrated within the nano-coacervates to improve stability in biofluids. Phenolic crosslinking at the liquid-liquid interface enables nano-coacervates to maintain exceptional structural integrity across various environments. The UCSD scientists discovered a pivotal polyphenol threshold for preserving enzymatic activity alongside enhanced stability. The disassembly rate of the nano-coacervates increases as a function of thrombin activity, thus preventing a coagulation cascade. This polyphenol-based approach not only improves stability but also opens the way for applications in biomedicine, protease sensing, and bio-responsive drug delivery. 

The implementation of ortho-quinone methide (o-QM) intermediates in complex molecule assembly represents a remarkably efficient strategy designed by Nature and utilized by synthetic chemists. o-QMs have been taken advantage of in biomimetic syntheses for decades, yet relatively few examples of o-QM-generating enzymes in natural product biosynthetic pathways have been reported. The biosynthetic enzymes that have been discovered thus far exhibit tremendous potential for biocatalytic applications, enabling the selective production of desirable compounds that are otherwise intractable or inherently difficult to achieve by traditional synthetic methods. Characterization of this biosynthetic machinery has the potential to shine a light on new enzymes capable of similar chemistry on diverse substrates, thus expanding our knowledge of Nature's catalytic repertoire.

Generation of drug-like molecules with high binding affinity to target proteins remains a difficult and resource-intensive task in drug discovery. Existing approaches primarily employ reinforcement learning, Markov sampling, or deep generative models guided by Gaussian processes, which can be prohibitively slow when generating molecules with high binding affinity calculated by computationally-expensive physicsbased methods. Researchers a UC San Diego have developed a new approach, named Latent Inceptionism on Molecules (LIMO), which significantly accelerates molecule generation with an inceptionism-like technique. LIMO employs a variational autoencoder-generated latent space and property prediction by two neural networks in sequence to enable faster gradient-based reverse-optimization of molecular properties.

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.

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.

The use of compound or fragment libraries are being increasingly used in drug discovery as rational drug design has become more sophisticated and high throughput techniques have made screening these types of libraries faster and less labor intensive.

As part of a comprehensive campaign to screen for effective vaccine adjuvants, 180,000 compounds were tested in a cell-based HTS screen to assess ability to activate NF-kB. Several classes of scaffolds bearing appropriate substitutions were found to stimulate innate immune responses and some of these scaffolds were structurally different from all other known ligands. More interestingly, the structure of one class of scaffolds challenges current dogma regarding what is necessary for efficacy.

SIO scientists have mined their rare collection of marine organisms to identify, characterize and analog a proprietary, small molecule with anti-cancer properties. SAR studies have identified regions of the molecule that have yielded analogs of greatest interest. Compositions of matter and methods of use are claimed for the treatment of cancer and hyperproliferative disorders.

Although treatment of cancer through non-surgical methods such as chemotherapy and radiation has dramatically improved survival rates, these therapies are associated with a fair degree of toxicity. The deleterious effects are particularly due to inability of these treatment methods to target cancer cells specifically without affecting surrounding normal cells. The challenge therefore, has been to find methods of selectively protecting normal cells, while maintaining susceptibility of cancer cells to therapy. Apoptosis triggered by chemotherapy and radiation is the most common cause of destruction of normal cells and is due to activation of a fully functional p53 protein present in these cells. p53 protein-induced transactivation of several genes involved in the apoptosis pathway leads to elimination of normal cells when exposed to anti-cancer agents. Therefore, therapeutic suppression of p53 directly or of its pathways leading to apoptosis, are attractive targets to prevent damage to normal cells during anti-cancer therapy. Earlier efforts in this area led to the isolation of a chemoprotectant, pifithrin that protected normal cells against radiation and chemotherapy-induced damage. However, this agent was not potent, was unstable and was not a specific inhibitor of p53-related apoptotic pathways. Hence, there is a clear need for new chemical inhibitors that are more robust, stable and specific as chemoprotectants of normal cells during anti-cancer therapy.

Cell growth and movement are controlled in part through the activation of a dual specificity phosphatase (DSP) called Slingshot-2 (SSH-2). SSH-2 is known to contribute to the progression of cancer and Alzheimer’s disease. Therefore, finding a specific inhibitor for SSH-2 may have a profound impact in clinical treatments of these diseases.

While inflammation is a beneficial component of the body’s response to harmful stimuli, prolonged or excessive inflammation triggers a wide variety of diseases. Current anti-inflammatory drugs (steroids, NSAIDs and immune selective anti-inflammatory derivatives) have undesirable side effects and for many indications including dermatology, drugs that act by a novel MOA may be more efficacious.

More than 60,000 people in the United States are diagnosed with lymphoma each year and the prognosis for those affected is usually poor. In many cases, patients may respond initially to first-line treatments (e.g. chemotherapy, radiotherapy), but subsequently suffer a relapse. In other cases, a patient may fail to respond to any treatment (refractory cancer). For patients diagnosed with relapsing cancers or patients resistance to conventional treatment, there are no optimal or preferred treatment options, resulting in a poor prognosis. Additional treatment options are needed for this group of lymphoma patients.

The past two decades has resulted in a marked increase in our knowledge about phospholipase A2 (PLA2) enzymes. The PLA2 superfamily of enzymes has been divided into four main types: secreted sPLA2s, cytosolic cPLA2s, calcium-independent iPLA2s, and lipoprotein-associated/PAF acetyl hydrolase LpPLA2s.The association of the different types of PLA2s with diverse indications has justified pharma’s interest in developing selective inhibitors to the specific types. Undeveloped indications exist in the central nervous system (CNS) and the ability to target these underserved indications would enable a new means for targeting the underlying inflammatory causes of numerous diseases.

Brief description not available

Brief description not available

A number of neurologic diseases, including Alzheimer's (AD), Huntington's, and Parkinson, are characterized by deposition of beta-amyloid plaques. These beta sheet-rich structures are formed from misfolded peptides or proteins that non-covalently self-aggregate to form oligomers, fibrils, and larger structures. The aggregation of beta-amyloid and other cellular proteins has been associated with beta-amyloid induced neurotoxicity in the pathogenesis of AD. Current therapeutic strategies are focused mainly on: Slowing down the production of beta-amyloid peptide. Preventing the growth of beta-amyloid fibrils. Disrupting the fibrils so that they disassemble into their beta-amyloid peptide components. An alternative strategy of coating the substrate fibrils with "neutralizing" small molecules may prevent or alleviate the symptoms of neuronal diseases associated with amyloid fibril or plaque formation.

Recent studies have revealed an important role for the enzyme phospholipase A2 (PLA2) in various aspects of inflammation in the peripheral and central nervous system. PLA2 consists of a superfamily of enzymes involved in the turnover of phospholipids; their metabolic products can induce both inflammation and demyelination. Therefore, PLA2 enzymes are good candidates as drug targets for the treatment.

Detection and quantification at the level of single molecules is the ultimate goal of analytical assays. This sensitive, platform technology could transform diverse fields, from environmental monitoring and medical diagnostics to the fundamental studies of chemical and biochemical processes. The early potential of synthetic, ion channel-forming peptides was has not been realized; one factor of many has been the inability to translate the technology to low cost, large scale production of stable and portable devices. The absence of generalized modalities for sensing a broad range of analytes left few incentives to clear the hurdles.