Multiple battles are being fought in the war against the SARS-CoV-2 coronavirus that causes COVID-19. Currently, there are nearly 5,000 clinical trials listed in the World Health Organization (WHO) database, either underway or in the recruiting stage, for vaccines and antiviral drugs. The Moderna mRNA vaccine and Janssen vaccine have received emergency use authorization (EUA) from the Food and Drug Administration (FDA); the Pfizer-BioNTech Vaccine (marketed as Comiraty) received FDA approval in August 2021.
Both the Moderna vaccine and Comiraty are mRNA-based, as opposed to most conventional vaccines against established diseases that are protein-based. Typically, the key ingredient in viral vaccines is either part of an inactivated virus, or one or more expressed proteins (antigens) that are a part of the virus. These protein antigens are responsible for eliciting an immune response that will fight future infection by the actual virus. Another approach is to use a replication-deficient viral vector (such as adenovirus) to deliver the gene encoding the antigen into human cells. This method was used for the coronavirus vaccine developed by Oxford University in collaboration with AstraZeneca; phase 3 interim data were announced on the heels of the Pfizer/BioNTech and Moderna announcements. All three vaccines target the SARS-CoV-2 spike protein, because it is the key that unlocks a path of entry into the host cell.
Cervical cancer is a major health problem for women, and it is currently the fourth most common cancer in women globally (1). A worldwide analysis of cancer estimates from the Global Cancer Observatory 2018 database showed that cervical cancer disproportionally affects lower-resource countries, on the basis of their Human Development Index; it was the leading cause of cancer-related death in women in many African countries (1).
Infection by human papillomavirus (HPV), a double-stranded DNA virus, is the leading cause of cervical cancer. Many types of HPV have been identified, and at least 14 high-risk HPV types are cancer-causing, according to a World Health Organization (WHO) fact sheet. Of these types, HPV-16 and HPV-18 are responsible for 70% of cervical cancers and pre-cancerous cervical lesions. HPV infection is sexually transmitted, most commonly by skin-to-skin genital contact. Although the majority of HPV infections are benign and resolve within a year or two, persistent infection in women, together with other risk factors, can lead to the development of cervical cancer [reviewed in (2)].
The development of NanoLuc® luciferase technology has provided researchers with new and better tools to study endogenous biology: how proteins behave in their native environments within cells and tissues. This small (~19kDa) luciferase enzyme, derived from the deep-sea shrimp Oplophorus gracilirostris, offers several advantages over firefly or Renilla luciferase. For an overview of NanoLuc® luciferase applications, see: NanoLuc® Luciferase Powers More than Reporter Assays.
The small size of NanoLuc® luciferase, as well the lack of a requirement for ATP to generate a bioluminescent signal, make it particularly attractive as a reporter for in vivo bioluminescent imaging, both in cells and live animals. Expression of a small reporter molecule as a fusion protein is less likely to interfere with the biological function of the target protein. NanoLuc® Binary Technology (NanoBiT®) takes this approach a step further by creating a complementation reporter system where one subunit is just 11 amino acids in length. This video explains how the high-affinity version of NanoBiT® complementation (HiBiT) works:
With the COVID-19 pandemic far from over in the United States and worldwide, the battle against the disease continues to intensify. Much hope has been pinned on vaccine development. However, vaccines are a long-term, preventative strategy. The immediate need for drugs to fight COVID-19 has accelerated efforts for a variety of potential treatments (see The Race to Develop New Therapeutics Against Coronaviruses).
The Remdesivir Origin Story
One drug that has received widespread attention is remdesivir. It was developed from research by Gilead Sciences that began in 2009, originally targeting hepatitis C virus (HCV) and respiratory syncytial virus (RSV) (1). At present, remdesivir is classified as an investigational new drug (IND) and has not been approved for therapeutic use anywhere in the world.
Transcriptional activation of genes within the nucleus of eukaryotic cells occurs by a variety of mechanisms. Typically, these mechanisms rely on the interaction of regulatory proteins (transcriptional activators or repressors) with specific DNA sequences that control gene expression. Upon DNA binding, regulatory proteins also interact with other proteins that are part of the RNA polymerase II transcriptional complex.
One type of transcriptional activation relies on inducing a conformational change in chromatin, the DNA-protein complex that makes up each chromosome within a cell. In a broad sense, “extended” or loosely wound chromatin is more accessible to transcription factors and can signify an actively transcribed gene. In contrast, “condensed” chromatin hinders access to transcription factors and is characteristic of a transcriptionally inactive state. Acetylation of lysine residues in histones—the primary constituents of the chromatin backbone—results in opening up the chromatin and consequent gene activation. Disruption of histone acetylation pathways is implicated in many types of cancer (1).
They existed 3.5 billion years before humans evolved on Earth. They’re neither dead nor alive. Their genetic material is embedded in our own DNA, constituting close to 10% of the human genome. They can attack most forms of life on our planet, from bacteria to plants to animals. And yet, if it wasn’t for them, humans might never have existed.
No, that’s not the blurb for a new Hollywood blockbuster, although recent developments have proven, once again, that truth is decidedly more bizarre than fiction. Now that “coronavirus” has become a household word, the level of interest in all things virus-related is growing at an unprecedented rate. At the time of writing, coronavirus and COVID-19 topics dominated search traffic on Google, as well as trends on social media. A recent FAQ on this blog addresses many of the questions we hear on these topics.
Our cells have evolved multiple mechanisms for “taking out
the trash”—breaking down and disposing of cellular components that are defective,
damaged or no longer required. Within a cell, these processes are balanced by
the synthesis of new components, so that DNA, RNA and proteins are constantly
Proteins are degraded by two major components of the cellular
machinery. The discovery of the lysosome in the mid-1950s
provided considerable insight into the first of these degradation mechanisms
for extracellular and cytosolic proteins. Over the next several decades,
details of a second protein degradation mechanism emerged: the ubiquitin-proteasome system
(UPS). Ubiquitin is a small, highly conserved polypeptide that is used to
selectively tag proteins for degradation within the cell. Multiple ubiquitin
tags are generally attached to a single targeted protein. This ill-fated, ubiquitinated
protein is then recognized by the proteasome, a large protein complex with
proteolytic activity. Ubiquitination is a multistep process, involving several
specialized enzymes. The final step in the process is mediated by a family of ubiquitin
ligases, known as E3.
Understanding the expression, function and dynamics of
proteins in their native environment is a fundamental goal that’s common to
diverse aspects of molecular and cell biology. To study a protein, it must
first be labeled—either directly or indirectly—with a “tag” that allows
specific and sensitive detection.
Using a labeled antibody to the protein of interest is a
common method to study native proteins. However, antibody-based assays, such as
ELISAs and Western blots, are not suitable for use in live cells. These
techniques are also limited by throughput and sensitivity. Further, suitable
antibodies may not be available for the target protein of interest.
In the fall of 1989, a small group of forensic scientists, law enforcement officials and representatives from Promega Corporation gathered in Madison, Wisconsin, for the very first International Symposium on Human Identification (ISHI). At the time, DNA typing was in its infancy and had not yet been validated as a forensic method. The available technology consisted of two methods: detection of restriction fragment length polymorphisms (RFLPs) and variable number of tandem repeats (VNTRs). Promega had developed products based on both analytical methods, which essentially provide a DNA “fingerprint” or profile for each individual tested.
Among the attendees at that first symposium was Tom Callaghan, then a graduate student. That experience made a significant impact on his career path. Last week, at ISHI 30, he presented a session on rapid DNA testing. Dr. Callaghan currently serves as a Senior Biometric Scientist for the FBI. In 1999, he was instrumental in launching the FBI’s Combined DNA Index System (CODIS) and in 2003, he became the first CODIS Unit Chief.
G protein-coupled receptors (GPCRs) are a large family of receptors that traverse the cell membrane seven times. Functionally, GPCRs are extremely diverse, yet they contain highly conserved structural regions. GPCRs respond to a variety of signals, from small molecules to peptides and large proteins. Many GPCRs are involved in disease pathways and, not surprisingly, they present attractive targets for both small-molecule and biologic drugs.
In response to a signal, GPCRs undergo a conformational change, triggering an interaction with a G protein—a specialized protein that binds GDP in its inactive state or GTP when activated. Typically, the GPCR exchanges the G protein-bound GDP molecule for a GTP molecule, causing the activated G protein to dissociate into two subunits that remain anchored to the cell membrane. These subunits relay the signal to various other proteins that interact with or produce second-messenger molecules. Activation of a single G protein can result, ultimately, in the generation of thousands of second messengers.
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