COVID-19 is still a global pandemic. Around the world, as of 5:40pm CEST, 20 June 2022, there have been 536,590,224 cumulative confirmed cases of COVID-19, including 6,316,655 deaths, reported to the World Health Organization. As of 16 June 2022, a total of 11,902,271,619 vaccine doses have been administered. The adoption of vaccines worldwide continues to increase, yet periodic spikes and surges in infection rates continue to occur with new SARS-CoV-2 variants, such as that observed in Australia over the past few months. Vaccine booster doses provide effective protection against developing severe disease and hospitalization, but vaccine adoption and distribution face ongoing challenges in low- and middle-income (LMIC) countries (1). Therapeutic interventions for those already infected are in development, with one (Paxlovid) currently available under emergency use authorization (EUA) in the US.
Cumulative COVID-19 statistics by country: WHO COVID-19 Dashboard. Geneva: World Health Organization, 2020. Available online: https://covid19.who.int/ (last cited: June 20, 2022).
Rectal cancer cases are rising in young adults (1). Typically, these cancers are treated with a multipronged approach that includes chemotherapy, radiation and surgery. These treatments show complete response in approximately 25% of patients and come with a long list of toxic side effects and life-altering complications including negative effects on bladder and bowel function, sexual health and fertility issues (2).
Approximately 5–10% of rectal cancers have deficiencies in their mismatch repair mechanisms (dMMR), and these cancers tend to be less responsive to standard chemotherapy treatments (2). Tumors are identified as dMMR using either immunohistochemistry (IHC) to detect the presence or absence of the major mismatch repair proteins, or by molecular testing for high-frequency microsatellite instability (MSI-H), the functional evidence of dMMR . These tumors often have somatic mutations that produce “foreign” proteins that can be detected by the immune system. As a result, these tumors are effective at priming an immune response and tend to respond well to immune checkpoint therapies such as PD-1 blockade treatments. Immune checkpoint blockade, or immune checkpoint inhibitor, therapies are a revolutionary, and relatively new, approach to treating cancer. Some tumors express immune checkpoints to prevent the immune system from producing a strong enough immune response to kill the cancer cells. Immune checkpoint blockade therapies work by blocking immune checkpoint proteins that act to negatively regulate the immune system through the PD-1 pathway. When these checkpoint proteins are blocked, the body’s T-cells can recognize and kill the cancer cells.
Biologic therapeutics such as monoclonal antibodies and biosimilars are complex proteins that are susceptible to post-translational modifications (PTMs). These chemical modifications can affect the performance and activity of the biologic, potentially resulting in decreased potency and increased immunogenicity. Such modifications include glycosylation, deamidation, oxidation and disulfide bond shuffling. These PTMs can be signs of protein degradation, manufacturing issues or improper storage. Several of these modifications are well characterized, and methods exist for detecting them during biologic manufacture. However, disulfide shuffling is not particularly well characterized for biologics, and no methods exist to easily detect and quantify disulfide bond shuffling in biologics.
Normally the cysteines in a protein will pair with a predictable or “normal” partner residue either within a polypeptide chain or between two polypeptide chains when they form disulfide bonds. These normal disulfide bonds are important for final protein conformation and stability. Indeed, disulfide bonds are considered an important quality indicator for biologics.
In a recently published study, Coghlan and colleagues designed a semi-automated method for characterizing disulfide bond shuffling on two IgG1 biologics: rituximab (originator drug Rituxan® and biosimilar Acellbia®) and bevacizumab (originator Avastin® and biosimilar Avegra®).
Squids are mysterious creatures roaming seas and oceans. They are also the subjects Urs Albrecht chose for his winning picture in the Swiss Art + Science competition, “One Out.” The photo shows squid juveniles, one of which displays striking colors in opposition to the rest. The bright individual is also physically removed from the group, may be scared or angry. The image is fascinating because we can see complex biology at play with the naked eye. Squids are Coleoid cephalopods, mollusks with arms attached to their heads. They have lost their shell and developed larger and highly differentiated brains and camera-type eyes through evolution. Their nervous system is highly organized. The central brain acts as the decision-making unit, and the peripheral nervous system processes motor and sensory information.
While PROTACs might not be the topic of conversation at high society cocktail parties, or merit cover stories in glamor magazines, they’re certainly shaking up the drug discovery industry. PROTAC® degraders, together with related compounds like molecular glues and LYTACs, are the basic tools for a targeted protein degradation strategy. Research in this field is advancing rapidly, enabling the development of therapies for disease targets disease targets previously thought to be “undruggable”. This blog post provides an overview of PROTACs based on frequently asked questions.
With use and time things wear out. Tires get worn on a car, and you have the old tires removed, recycled, and replaced with new ones. Sometimes a part or piece of something isn’t made properly. For instance, if you are assembling a piece of furniture and you find a screw with no threads, you throw it out and get a screw that was made properly. The same thing holds true for cells. Components wear out (like tires) or get improperly made (a screw with no threads), or they simply have a limited lifetime so that they are available in the cell only when needed. These used and worn components need to be removed from the cell. One system that allows cells to recycle components and remove old or improperly functioning proteins is the Ubiquitin-Proteasome System (UPS). The UPS system relies on a series of small peptide tags, ubiquitin, to mark a protein for degradation. Researchers are now harnessing the UPS to target aberrant proteins in diseased cells through PROteolysis TArgeting Chimeras or PROTACs. PROTACs hold promise as highly efficacious therapeutics that can be directed to eliminate only a single protein. To take full advantage of the power of PROTACs, researchers need to understand the molecular underpinnings that are responsible for successful protein degradation. Here we review a paper that seeks to develop a computer model for predicting whether PROTAC ternary complex formation leads to ubiquitination and successful degradation of a target protein.
Addressing the Intractable Target
Research to understand diseases including cancers, neurodegeneration, and auto-immune conditions has revealed that in many disease states, affected cells produce growth factors or enzymes that are constitutively active (“always on”). These proteins are targets for small molecule inhibitors that bind specific sites preventing the constitutive activity or signaling. More recently, biologics, or protein-based therapeutics, including monoclonal antibodies (mAb), have been developed that can bind and block inappropriate signaling pathways, especially those that allow cancer cells to escape immune system surveillance.
Unfortunately, up to 85% of targets have proven intractable to small molecule inhibitors, or they are not suitable for a biologics approach. Oftentimes, the target protein doesn’t have a great place to bind a small molecule, so even though inhibitors might exist they cannot bind well enough to be effective. Or, as in the case of many cancers, the diseased cell manages to overcome the effect of the inhibitor by overexpressing the target. Still other aberrant proteins associated with diseases haven’t gained function to cause a disease; they have instead, lost function, so designing an inhibitor of the protein is not a workable strategy. Enter the PROTAC.
G protein-coupled receptors (GPCRs) comprise a large group of cell surface receptors, characterized by the unique structural property of crossing the cell membrane seven times. They respond to a diverse group of signaling molecules, such as peptides, neurotransmitters, cytokines, hormones and other small molecules (1). Upon activation, GPCRs interact with GTP-binding (G) proteins and arrestins to regulate a wide variety of signaling pathways. This broad range of functions makes GPCRs attractive targets for drug discovery. The importance of GPCR research was highlighted in 2012, with the Nobel Prize in chemistry being awarded to Robert Lefkowitz and Brian Kobilka “for studies of G-protein–coupled receptors”.
Based on structure and function, GPCRs are categorized into six classes, A–F. The class A GPCRs, or rhodopsin-like receptors, have been studied extensively due to their association with many types of diseases (2). Within the class A GPCRs is a group that share a highly conserved structural motif (3) and respond to chemokines—small “chemotactic cytokines” that stimulate cell migration, especially that of white blood cells (4). A subfamily of class A GPCRs respond to chemokines that have two cysteine residues near the N-terminus, known as CC chemokines. GPCRs activated by CC chemokines are called CC chemokine receptors or CCRs, and these interactions have been implicated in both pro- and anti-cancer pathways (5).
A new study, published in the Journal of Molecular Diagnostics (1), highlights the potential of using long mononucleotide repeat (LMR) markers for characterizing microsatellite instability (MSI) in several tumor types. The paper is a result of a collaborative effort between researchers from Johns Hopkins University and Promega to evaluate the performance of a panel of novel LMR markers for determining MSI status of colorectal, endometrial and prostate tumor samples.
Microsatellite instability (MSI) is the accumulation of insertion or deletion errors at microsatellites, which are short tandem repeats of DNA sequences found throughout the genome. MSI in cancerous cells is the result of a functional deficiency within one or more major DNA mismatch repair proteins (dMMR). PCR-based MSI testing is a commonly used method that can help understand a tumor’s genomic profile as it relates to MMR protein function.
Historically, MSI has been a biomarker associated with Lynch syndrome, the hereditary predisposition to colorectal and certain other cancers. In recent years, research interest in MSI has exploded, driven by the discovery that its presence in tumor tissue can be predictive of a positive response to anti-PD-1 immunotherapies (2,3).
We’re entering the third year of the global COVID-19 pandemic, and it’s far from over. There has been considerable progress with SARS-CoV-2 vaccine development, with most of the focus on mRNA vaccines and adenoviral vector vaccines. Meanwhile, novel vaccine delivery systems are being tested among efforts to develop a “pan-coronavirus” vaccine that is effective against multiple variants. One such example is ferritin nanoparticle technology developed by researchers at the Walter Reed Army Institute of Research and their collaborators. Encouraging results from nonhuman primate studies, using several SARS-CoV-2 antigens, were published in 2021 (1–3).
The current surge in COVID-19 cases that began last month is largely due to the Omicron variant in the US, according to data from the US Centers for Disease Control and Prevention (CDC). At present, we still don’t know enough about this variant, but it’s clear that its rapid spread is forcing us to re-examine what we know about SARS-CoV-2 (4). As the virus continues to mutate, new variants will continue to emerge and spread. Although current vaccines can provide protection against multiple variants, breakthrough infections are a concern. Vaccination is still the best option to reduce the risk of infection, hospitalization, and death compared to unvaccinated people.
It’s clear that vaccines are only part of an effective response to fighting the pandemic. Along with continued vaccine development efforts, attention must also be given to antiviral drug development for people already infected with COVID-19. Due to the lengthy process for new drug development, early efforts focused on repurposing existing drugs.
In the past decade, there has been a sharp rise in studies using spheroids as cell models for basic research and drug discovery. Spheroids are self-organized aggregation of cells that form a spherical mass, and they have become widely popular because they are much more physiologically relevant compared to flat 2D cell cultures.
In spheroids, the inner cells have less access to nutrients and oxygen compared to the outer layer, forming a natural gradient. As a result, metabolite concentration and cellular state such as proliferation and differentiation, can be very different at the periphery compared to the inner core. This phenomenon, known as “heterogeneity”, makes 3D tumor spheroids much more representative of actual tumors in the human body.
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