Cannabinoids are naturally occurring compounds isolated from the Cannabis sativa plant. The two best-known cannabinoids are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is the psychoactive component of Cannabis associated with the “high.” There is an abundance of information available about THC and its derivatives, so this blog is focused on lesser-known cannabinoids, their key benefits from the scientific literature, and a deeper view into their chemical structures.  

There has been a massive increase in products on the market containing CBD: oils, beauty and skin care products, therapeutic agents, beverages, chocolates, gummies, and even dog treats. This blog is not an endorsement of any of these products, and it is important to note that Cannabis is illegal at the federal level and is a schedule class I drug. However, as people are consuming these products, which are mostly marketed as “dietary supplements” and therefore no need for Food and Drug Administration (FDA) approval, it is crucial to understand their impact on human health.

Research trends in cannabinoids

Using cannabidiol (CBD) as a model cannabinoid to investigate the current research on therapeutic perspectives for cannabinoids, a quick search in CAS SciFinder yields less than 5K references.

A deeper dive into the results show that human clinical studies only comprise less than 200 documents and all pre-clinical (animal, in vivo, in vitro, ADME, and in silico) studies have less than 550 results. This perhaps indicates an opportunity for drug companies, cosmetic manufacturers, nutrition organizations, and other businesses to further advance cannabinoid research for the benefit of humankind.  

How do cannabinoids enter our bodies?

There are four major routes of administration:

• Inhalation
• Sublingual
• Ingestion
• Topical

One of the most popular forms of consuming cannabinoids is smoking plant material or vaping a cannabinoid oil, basically inhalation. When the cannabinoids enter the lungs, they are absorbed quickly and rapidly eliminated from the body. Inhalation tends to be a preferred method for consuming Cannabis.

Another route of administration is sublingual, where oils or tinctures containing cannabinoids are placed under the tongue are absorbed directly into the bloodstream. This method allows for faster and longer-lasting effects. Cannabinoids can also be ingested. The body will metabolize the edible forms, but this can take considerably longer to achieve the desired effects. Cannabinoids can also be used as topical agents like creams, lotions, sprays, patches, or balms. Absorption is preferred by those people who may be treating sore muscles or skin problems. Cannabinoids are absorbed through the skin directly into the bloodstream.

While THC is most widely known, a deeper understanding of the chemical structures of non-psychoactive cannabinoids like CBD, CBG, CBN, and CBC and their effects provides insight into the emerging landscape of products. 

Cannabidiol (CBD)

After THC, cannabidiol (CBD) is probably the most well-known cannabinoid. CBD is derived directly from the hemp plant and has no psychoactive activity. The legality of CBD is constantly in flux and each state has ever-evolving legislation regulating CBD. Harvard Medical School recognizes CBD can be used to treat anxiety, insomnia, chronic pain, arthritis, and addiction. Most importantly, CBD is a component in FDA-approved drugs to treat serious childhood epileptic diseases (ex. Epidiolex). The main side effects of CBD are nausea, fatigue, and irritability. Remember, products containing CBD are not FDA regulated and may contain impurities and unknown dosages. Exercise caution and always purchase CBD products from reputable sources. 

Cannabigerol (CBG)

While CBG was discovered in 1964, it is used less often than CBD or THC because it is found in very low concentrations in the Cannabis plant. CBG interacts with the cannabinoid receptors in our body, namely CB1 and CB2. When the CBG attaches to these receptors, it increases neurotransmitters which affect motivation, appetite, sleep, pleasure, and pain. CBG can also affect serotonin and adrenoceptors. These receptors also control neurotransmitters—CBG is sometimes called the “bliss” molecule due to the increase in neurotransmitters. Cannabigerol has been shown to have antibiotic effects and can reduce intraocular eye pressure. 

Cannabinol (CBN)

Cannabinol is not directly synthesized by the Cannabis plant; CBN is a metabolite resulting from a breakdown of THC. When the plant material is exposed to oxygen and time, CBN can increase as the THC degrades. CBN is a sedative and therefore, helps with insomnia. CBN is not well-researched, but some studies showed cannabinol to have antibiotic effects, eased glaucoma, and stimulated the appetite. In mice, CBN was shown to delay the onset of Amyotrophic Lateral Sclerosis (ALS). This promising compound offers many opportunities for researchers to pursue therapeutic uses for CBN. 

Cannabichromene (CBC)

CBC is derived from CBG and has demonstrated powerful antimicrobial effects, especially in infections that have been resistant to other antibiotic treatments. In addition, some studies in rats have shown CBC to have neuroprotective effects that protect the brain from neurodegenerative conditions (Alzheimer’s Disease) and even encourage the brain to grow new cells. 

CBC does not bind well with the cannabinoid receptors, but it does bind with vanilloid receptor 1 (TRPV1) and transient receptor potential ankyrin 1 (TRPA1), which are known to affect pain perception. CBC has also shown anticancer properties. Again, there is not much data on CBC as a therapeutic agent in human studies, but in preliminary research, the identified properties seem to promote further investigation. 

The Entourage Effect

Many Cannabis products advertise “full-spectrum” CBD, meaning that the product not only contains CBD, but can also contain the other cannabinoids discussed here, as well as terpenes, essential oils, and up to 0.3% THC (legislated). Using these cannabinoids in conjunction with one another to increase potency and effectiveness, differing from the effects of each chemical on its own, culminates in a theory called the “Entourage Effect”. Without getting too technical, the proposed mechanism of the Entourage Effect involves inactive lipids combined with exogenous cannabinoids that increase the activity of endogenous cannabinoids (anandamide and 2-arachidonylglycerol). Research is new in this area, but some studies have shown positive results in cancer, mood and anxiety disorders, movement disorders, and epilepsy.

Future perspective and impact

Cannabinoids may have a bad rap because of their association with marijuana and the psychoactive effects of THC and its derivatives. Legal concerns may dissuade researchers from pursuing cannabinoid research, however, initial studies on cannabinoids have clear data there could be potential therapeutic benefits for these compounds, both as single components and through activating our endogenous cannabinoids and the “Entourage Effect.” This blog only addressed some of the more known cannabinoids but recall there are over 100 of these compounds identified and more to be discovered! Hopefully, with continued research, the stigma surrounding these cannabinoid substances will dissipate, and their full potential can be actualized in their treatment of debilitating diseases. 

The emerging trend of increased research in recreational drugs for mainstream health benefits goes far beyond cannabinoids, see how psychedelics like LSD, Molly, and "shrooms" could be next in the fight against depression and PTSD.

Many technologies have been researched with an eye toward enabling a hydrogen economy. In the field of hydron utilization in fuel cells, numerous materials have been created to target higher efficiencies and applications.

This peer reviewed publication details the progress of hydrogen energy research from 2011 to the latest emerging trends. The primary elements of this study are catalyst materials that allow the green production of hydrogen and materials used in technical capacities in relation to fuel cells. An in-depth examination of the landscape of hydrogen economy research is also given.

With no carbon emissions and 3 to 10 times more energy density than fossil fuels, renewable hydrogen has the potential to end our fossil fuel dependency in the future.  Yet today 96% of hydrogen production is through fossil fuels and is not sustainable.  Our landscape view of the green hydrogen economy (production, storage, and utilization) highlights emerging trends and unique opportunities in this space.  

It’s been years in the making, but the promise of messenger (m)RNA vaccines has finally been realized, thanks to a global pandemic that accelerated research and innovation in the field. But the success of mRNA vaccines would not have been possible without another lynchpin technology — the lipid nanoparticles (LNPs) that protect mRNA and deliver it into cells. This article will discuss the landscape of lipid nanoparticle research and future opportunities for nanotechnology beyond COVID-19.

Learn more about the journey from liposomes to lipid nanoparticles in our Insight Report on nanotechnology and its application in drug delivery, the role it plays in enabling the RNA revolution, and the opportunities ahead in cosmetics, agriculture, and beyond.

Nanotechnology and mRNA vaccines — a success story?

While several vaccines have been deployed in the fight against SARS-CoV-2, the two lipid nanoparticle-based mRNA vaccines from Moderna and Pfizer–BioNTech have been the most widely used, demonstrating the pivotal role of nanotechnology in the response to the COVID-19 pandemic. The large-scale rollout of these vaccines in 2021 changed the course of the pandemic, causing a remarkable decline in COVID-19 cases.

However, due to the rapid spread of the virus, several new variants of SARS-CoV-2 have arisen and are expected to emerge, creating an enormous public health challenge. Variants of concern such as Delta and Omicron have impacted vaccine efficacy by reducing the function of neutralizing antibodies. Yet, nanotechnologies may hold the key to tackling the SARS-CoV-2 variant challenge. Scientists are currently exploring various ways of utilizing nanotechnology for this purpose, including nanoparticle, vaccine-elicited, neutralizing antibodies, engineered neutralizing antibodies, and “nanodecoys”. The latter approach involves creating decoy nanoproteins that interact with the angiotensin-converting enzyme-2 (ACE2) receptor expressed on cells, inhibiting the binding of the virus to ACE2, and protecting host cells from infection. As these nanotechnologies are deployed to hasten the end of the novel coronavirus pandemic, how can we apply the learnings from this intense research effort to other areas of unmet need, including other global infectious diseases?

The development of lipid nanoparticle technology

Before we look to the future, let’s revisit the history of lipid nanoparticle technology. It all began in 1965 with the discovery of liposomes: closed lipid bilayer vesicles that spontaneously self-assemble in water to form fatty capsules. Researchers immediately saw their promise in drug delivery due to their ability to encapsulate small-molecule drugs and enhance their aqueous solubilities (it is known that over 40% of these agents exhibit low solubility in water). Since the initial discovery of liposomes, the technology has been continually tweaked and refined, optimizing the functionality of lipid nanoparticles to create extremely versatile drug delivery platforms and liposomal drugs.

Although currently in the spotlight as a vital component of the COVID-19 mRNA vaccines, lipid nanoparticles have been successfully utilized as drugs for decades. In 1995, Doxil , an LNP-based formulation of the antitumor agent doxorubicin, became the first approved liposomal drug. Another liposomal drug, Epaxal, is an LNP formulation of a protein antigen used as a hepatitis vaccine. Hot on the heels of this advancement, 2018 saw the US Food and Drug Administration’s approval of Onpattro (patisiran), an LNP-based short interfering RNA for the treatment of polyneuropathies induced by hereditary transthyretin amyloidosis. This pivotal milestone paved the way for the clinical development of many nucleic acid-based therapies enabled by nanoparticle delivery (see Fig. 1 for a timeline of key lipid nanoparticle advancements and our Insight Report for a more detailed view).

Nanotechnology in a post-COVID world

A recent analysis of the CAS Content Collection™ explored the unique landscape of lipid nanoparticle- related research. The analysis revealed that of more than 240,000 LNP-related scientific publications in the CAS Content Collection™, more than 190,000 are from the period of 2000–2021, highlighting the growing interest in nanotechnology. It is predicted that this will be further bolstered by the application of nanotechnology in tackling infectious diseases in light of COVID-19, with the nanomedicine market predicted to reach over $164 billion by 2027.

While lipid nanoparticles have long held a recognized position in the mainstream of drug delivery systems, the technology has not been without its limitations. Liposomes — considered the first generation of LNPs — require complex production methods using organic solvents, exhibit low efficiency at entrapping drugs, and are difficult to perform on large scales. While key nanotechnology advancements, such as the development of solid lipid nanoparticles and nanostructured lipid carriers, have helped overcome these issues (see Table. 1), challenges remain. Manufacturing costs, extensibility, safety, and the intricacy of nanosystems must all be assessed and balanced against any potential benefits. To help overcome the current limitations of this technology, researchers are now looking to the next generation of lipid nanoparticles, exploring more sophisticated delivery systems with enhanced capabilities.

Table 1: Types of lipid nanoparticles: structure and role 

The successful application of nanotechnology to COVID-19 mRNA vaccines has led to renewed interest in this technology for treating infectious diseases such as malaria, tuberculosis (TB), and human immunodeficiency virus (HIV), among others. Nanotechnology has the potential to transform both the detection and treatment of these diseases. The versatility of the technology means that treatments encapsulated in liposomes, polymer nanoparticles, and nanodrug crystals can be delivered locally or systemically for sustained or immediate release. The possibilities are endless.

However, while some infectious diseases (e.g., HIV) have been the focus of intense research, others such as malaria and TB have been pursued with less enthusiasm. Funding (or lack thereof) has historically been a limiting factor in the progress of nanotechnologies in these areas of unmet need. However, that may be set to change. A team at Johns Hopkins is developing a platform to speed up the design of lipid nanoparticles for gene medicine delivery, making the process more affordable. The team is now leveraging this technology to develop a malaria vaccine that targets the disease-causing parasite during its lifecycle in the liver.

The future is bright for nanotechnology

Nanotechnology has revealed a new horizon in science, particularly in medicine. The use of lipid nanoparticles as a delivery vector for the COVID-19 mRNA vaccines will likely expand the scope for further research. More sophisticated and multifunctional nanocarrier designs are set to address current and future unmet needs.

See our Insight Report for a more detailed landscape analysis of the past, present, and future opportunities for lipid nanoparticle technologies.

NASA’s Artemis Program is an incredible return back to the moon that may redefine how future humans will eat both in space and on Earth. Seven plant-focused experiments have been approved to understand the different requirements to successfully grow plants in space. In addition to space agriculture, new innovations like 3D printed food, packaging, and novel applications of microbiomes could have major implications for food on Earth. The design challenges of food in space (longevity, closed-loop cycles, nutrition, and inability to cook) can improve access to nutrition in Earth’s challenging environments.  

What is needed for food in space?

While most of us on Earth are focused on variety and nutrition in our diets, a few key criteria for space food systems are:

1. Food safety: preventing food spoilage, waste-processing, and recycling with advanced closed-loop ecosystems for plant growth
2. Reliability:  has capability to withstand the harsh conditions found in space, a long shelf life, and requires minimal space.
3. Nutrient density and enjoyment (palatable, varied, easily prepared etc.)

Space has unique challenges

Growing plants in space has some challenges due to it being a closed ecosystem with no gravity, no direct sunlight, limited space, and limited water supply. The absence of gravity means cooking is difficult and must minimize the strain of resources on the shuttle (mass, power, crew time, water, waste disposal). Prepackaged foods are not always feasible due to the deterioration of nutrients and enormous quantities required. In the future, deep space exploration will require years of travel with a limited supply of food and water and no possibilities of resupplying.

Publication and patent trends

Publications and patents by NASA and other agencies on space food have been ongoing for decades. Using the CAS Content Collection™, we looked at global scientific publications related to space food and life systems between 2000 and 2022.The research landscape shows that large announcements of new space programs drive an increase in future publications and patents across the globe. For example, the International Space Station has been making a massive effort since it was first announced in 1993.The increase in publications and patents since then is highly correlated to the over 2,500 experiments done since. Similarly, there is a clear trend of increasing research after NASA’s Commercial Crew Program was announced in 2011 and a corresponding bump after the Artemis Program in 2017 (Figure 1).

New solutions: 3D printed space food

Out of this world pizza? Pardon the pun, but new advances in 3D printing food on the International Space Station could have a massive impact on some of the biggest food challenges we have on Earth.  3D printers now produce different designs and customized diets by adding specific ingredients into food. Today Inks for the 3D printer can consist of dried meat, vegetables, and dairy powders, fortified with relevant micronutrients. Some of the most common printable edible inks are mashed potatoes, chocolate, dough, cheese, cream, cake frosting, and fruits.

This technology is crucial for extending the shelf life of space food. It allows the food material to be sterile and stored in raw material form. Additionally, this minimizes storage space on board.

Using microbes to produce nutrients

Researchers are looking into different types of bacteria to convert air components or body waste into nutrients. For example, bacteria — known as hydrogenotrophs (single-celled microorganisms that metabolize hydrogen for energy) — could convert astronauts’ exhaled carbon dioxide into proteins in a fermentation type of process. Other researchers found that Yarrowia lipolytica, a relative of baker's yeast, can be used to make lipids and even plastics by feeding them with human urine opening the possibility of turning natural waste into nutrients essential to human health.

Prepackaged food

While dried or frozen foods are critical, NASA is looking into emerging food preservation technologies for new approaches. For example, the Pressure Assisted Thermal Sterilization and Microwave Sterilization ensures higher initial quality and nutrition in prepackaged food. Researchers are also investigating better packaging to increase food shelf life for up to 5 years.

Closed-loop systems and space farming

The best option for a good and constant source of proper nutrition relies on farming aboard the spaceship. The existence of a space farm would aid the creation of a sustainable environment, as plants can be used to recycle wastewater, generate oxygen, purify the air, and even recycle feces on the spaceship. Currently, there is a space garden, known as Veggie, that is. It can hold six plants and was used to successfully grow lettuce, Chinese cabbage, mizuna mustard, red Russian kale, and zinnia flowers. A list of the plants that were grown in space over the past four decades can be found here.

Real-world implications for space food

Research in this area of space food leads to a better and more sustainable relationship between our food and planet. Closed-loop greenhouses and vertical farming can be utilized in arid, polar, remote, or in highly populated areas due to their low water and land requirements. Producing meat by using air components could reduce livestock and require a lot less land and water usage. An enhanced air purifier created for space food is now currently used for food preservation and in operating rooms.

3D printing of food could play a role in alleviating food shortages here on Earth. 3D printers can be used to create food faster and cleaner than any chef could do, while also customizing nutrition values and textures. The edible inks can also broaden the use of non-traditional sources of food material.

All these technologies can reduce the transport volume, packaging, distribution, and other costs by moving closer to the customers, hence decreasing ecological footprint. The benefits of continued research on space exploration thus extend to Earth’s environment and its inhabitants providing ideas on maintaining and preserving terrestrial ecosystems.

Sugars are not only crucial for normal physiological processes in the cell, but they also play an essential role in pathological processes. Bacteria and viruses can even recognize them to infect their hosts. While they remain an elusive research topic, the field of glycobiology has gained much interest in recent years from researchers from a range of disciplines. One such tool is bioorthogonal chemistry, which can be used for imaging glycans, the carbohydrate structures attached to proteins and peptides (Figure 1). 

Recently, Carolyn Bertozzi's research group used bioorthogonal chemistry to make the stunning discovery of a new biomolecule, glycoRNA, which has been pioneering research in the field of bioorthogonal chemistry for many years. Here, we dive into the world of bioorthogonal chemistry and its applications, particularly how it has helped move the field of glycobiology forward and what opportunities lie ahead.

What is bioorthogonal chemistry?

The term bioorthogonal chemistry was coined by Bertozzi's research group, which has been pioneering the field for many years. Bioorthogonal chemistry is a set of reactions that can take place in biologic environments with minimum effect on biomolecules or interference with biochemical processes. The process of bioorthogonal chemistry fits the stringent criteria needed for reactions to occur as they should in biologic systems:

• Reactions must occur at the temperatures and pH of physiological environments.
• Reactions must provide products selectively and in high yields and must not be affected by water or endogenous nucleophiles, electrophiles, reductants, or oxidants found in complex biologic environments.
• Reactions must be fast, even at low concentrations, forming stable reaction products.
• Reactions should involve functional groups not naturally present in biologic systems.

What is bioorthogonal chemistry used for?

The CAS Content Collection^TM has allowed us to analyze publication trends in bioorthogonal chemistry applications from 2010 to 2020 (Figure 2). Imaging was the single biggest use of bioorthogonal chemistry between 2010 and 2020, followed by drug development and delivery.

(*2010 was selected as an initial reference point because it was the first year the number of documents containing "bioorthogonal chemistry" increased significantly relative to the previous year. Approximately 90% of the total number of documents containing the term "bioorthogonal" or "bio-orthogonal" have been published since 2010.)

Furthermore, protein bioorthogonal chemistry represents the highest number of publications, likely because these methods are the most established, with other fields steadily increasing as well, including the relatively new field of glycans (Figure 3).

Glycan imaging

Bioorthogonal chemistry has proven to be an essential tool for understanding the structures, localization, and biological functions of glycans. Glycans are oligosaccharides attached to peptides, proteins, and lipids commonly found in cell walls, allowing their use in visualizing cell types selectively. Glycan metabolic precursors include many bioorthogonal functionalities, including azides, terminal alkynes, and strained alkynes. The glycans can be visualized using the appropriate bioorthogonal partner, e.g., azides are seen with phosphine-containing esters or thioesters by Staudinger or traceless Staudinger ligations, terminal alkynes or strained alkynes are identified using CuAAC or SPAAC, respectively.

Bioorthogonal chemistry moving glycobiology forward

Until now, RNA has not been a major target of glycosylation; however, a significant recent finding made possible using metabolic labeling and bioorthogonal chemistry was the discovery of "glycoRNA." Using a battery of chemical and biochemical approaches, Dr. Ryan A. Flynn led a Bertozzi research group that found that conserved small noncoding RNAs bear sialylated glycans and that these glycoRNAs are present in multiple cell types and mammalian species in cultured cells and in vivo.

The strategy used for this discovery was to metabolically label cells or animals with precursor sugars functionalized with a clickable azide group. Azidosugars enable bioorthogonal reaction with a biotin probe for enrichment, identification, and visualization after incorporation into cellular glycan. Using an azide-labeled precursor to sialic acid, peracetylated N-azidoacetylmannosamine (Ac4ManNAz), highly purified RNA preparations from labeled cells were found to exhibit azide reactivity. The assembly of glycoRNA is dependent on canonical N-glycan biosynthetic machinery and results in structures enriched in sialic acid and fucose. Further analysis of living cells revealed that the majority of glycoRNAs were present on the cell surface where they interact with anti-dsRNA antibodies and members of the Siglec receptor family. Further research is warranted to investigate the role of glycoRNA.

With the help of bioorthogonal chemistry, a direct interface between RNA biology and glycobiology was established, and there are now plenty of other discoveries to be explored.

What opportunities does the future of bioorthogonal chemistry hold?

Bioorthogonal chemistry has a wide range of applications in science and medicine and has been used to progress research significantly in recent years. In addition to propelling the field of glycosylation forward through the discovery of glycoRNAs, it has shown promising applications in drug delivery and drug targeting, and its use is likely to expand further in the future. Some examples include:

• In situ synthesis of pharmaceutical agents: Bioorthogonal chemistry may be helpful in assembling drugs from smaller precursors. By creating drugs as and when needed, drugs could thus be more effective and less toxic; the scope of pharmacologic intervention could also be expanded.
• Glycan labeling: Lipid nanoparticles have been generated containing azide-labeled galactosamines using folate ligands. Owing to the presence of increased folate receptors in tumor tissue, LNP internalization occurred, followed by cargo release into the tumor cells. Tumor membranes incorporated azide-functionalized dibenzocyclooctyne, triggering an immune response when tumor cells were exposed to human sera.
• Click to release: This method uses bioorthogonal chemistry to control the timing and location of drug release, resulting in a drug that should be selectively toxic to target cells.

With continued development and refinement of reactions, bioorthogonal chemistry will be an important tool for further research.

See our article in Bioconjugate Chemistry and related CAS Insights Report for more details about bioorthogonal chemistry and its wide range of applications. 

Since the outbreak of the novel coronavirus disease COVID-19, caused by the SARS-CoV-2 virus, this disease has spread rapidly around the globe. Scientists and physicians have been racing to understand this new virus and the pathophysiology of this disease to uncover possible treatment regimens and discover effective therapeutic agents and vaccines.

To support the current research and development, CAS has produced a special report to provide an overview of published scientific information with an emphasis on patents in the CAS content collection. It highlights antiviral strategies involving small molecules and biologics targeting complex molecular interactions involved in coronavirus infection and replication. The drug-repurposing effort documented herein focuses primarily on agents known to be effective against other RNA viruses including SARS-CoV and MERS-CoV. 
 

The patent analysis of coronavirus-related biologics includes therapeutic antibodies, cytokines, and nucleic acid-based therapies targeting virus gene expression as well as various types of vaccines. More than 500 patents disclose methodologies of these four biologics with the potential for treating and preventing coronavirus infections, which may be applicable to COVID-19. The information included in this report provides a strong intellectual groundwork for the ongoing development of therapeutic agents and vaccines.

The angiotensin-converting enzyme 2 (ACE2) protein has drawn considerable attention in recent years for its role as a receptor of the SARS-CoV-2 virus, but the flurry of research into ACE2 has also revealed intriguing possibilities for it as a therapeutic target in a number of other diseases.

What is ACE2?

ACE2 is a membrane protein with an enzymatic domain located on the outer surface of human cells. It was so named because this protein was initially identified as a homolog (or a variant) of angiotensin-converting enzyme (ACE), an enzyme that mediates the formation of the peptide hormone, angiotensin II from angiotensin I. ACE has been studied extensively and is a well-known vasoconstrictor (i.e., it causes muscle contraction in the blood vessel wall and narrowing of the blood vessel lumen). 

ACE2, now known to be a viral receptor, also acts as a vasodilator, which counterbalances ACE and causes blood vessel walls to relax. Both ACE and ACE2 are important players in the renin-angiotensin system (RAS) that regulates blood pressure and blood flow to multiple organs, including the lungs, heart, and kidneys.

Functions of the angiotensin-converting enzyme 2

The renin-angiotensin system encompasses a complex network of enzymes, peptide hormones, and receptors, as shown in Figure 1. Angiotensinogen, the angiotensin (Ang) precursor, secreted by the liver, is cleaved by the kidney enzyme renin to produce Angiotensin I (Ang I). Ang I is then converted to Ang II by ACE. Ang II, an eight-amino acid hormonal peptide, binds to type 1 angiotensin receptors (AT1R) on the surface of muscle cells in small blood vessels to cause vasoconstriction. It also promotes sodium reabsorption by the kidneys. Both vasoconstriction and sodium reabsorption lead to an increase in blood pressure. Thus, abnormally high ACE activity leads to increased levels of Ang II, causing hypertension.

Conversely, ACE2 catalyzes the conversion of the eight-amino acid peptide, Ang II, to a seven-amino acid peptide (Ang 1-7), which appears to have the opposite effect of Ang II via its action on a different receptor, called Mas receptor (MasR). While the precise role of Ang 1-7 in blood pressure regulation has not been fully elucidated, evidence exists that it lowers blood pressure and induces vasodilation. In addition, ACE2 cleaves Ang I to Ang 1-9, and therefore may further counterbalance the effect of ACE by removing its substrate. By causing the conversion of Ang II to Ang (1-7) and Ang I to Ang 1-9, ACE2 may play a role in maintaining the balance between vasoconstriction and vasodilation to keep blood pressure in check. 

The role of ACE2 in SARS-CoV-2 infection

Since the outbreak of COVID-19, scientists have been racing to understand the SARS-CoV-2 virus, elucidate the mechanism for disease progression, and identify treatment options. Extensive research has been devoted to identifying viable genes and proteins as targets for therapeutic agents and, early in the pandemic, a potentially important role for ACE2 as a receptor for the the SARS-CoV-2 virus was discovered.

ACE2 can be recognized by the spike protein (S protein) on the surface of the SARS-CoV-2 or SARS-CoV virus. ACE2 and S protein bind in a fashion analogous to a lock-and-key interaction, which enables the virus to enter human cells (Figure 2).

Although SARS-CoV-2 is very similar to SARS-CoV, the virus that caused SARS (severe acute respiratory syndrome), a few mutations in the receptor binding domain of the S protein have significantly increased the SARS-CoV-2 virus’ binding affinity to ACE2. These differences may underpin the higher transmissibility of COVID-19. There is evidence that ACE2 is expressed in our lungs, digestive systems, hearts, arteries, and kidneys. ACE2 expression also increases with age and is higher in patients suffering from cardiovascular diseases, potentially explaining the increased severity of COVID-19 in these subgroups.

ACE2 protein interactions in COVID-19 therapies

While functioning as the docking site for SARS-CoV-2 and mediating virus entry into the host cells, ACE2 may not act alone in this process. Other host enzymes are also involved in facilitating viral entry. Enzymes called proteases are responsible for removing fragments both from ACE2 and S proteins to enhance their interaction process. Other enzymes modify the ACE2-S protein complex packed in membrane-bound vesicles to facilitate viral entry into the host cell. Therefore, ACE2 and its interaction with SARS-CoV-2, as well as other proteins involved in this process, are conceivably valid targets for anti-COVID-19 agents.

Upon viral binding, it is speculated that the catalytic domain of ACE2 may be blocked by the virus, resulting in limited access to the substrate, Ang II, causing Ang II accumulation. Additionally, with viral entrance, the surface ACE2 may be internalized to the cells, therefore decreasing ACE2 enzymatic function (Figure 3). As a result of reduced ACE2 activity, circulating Ang II levels may increase, as has been reported in COVID‐19 patients. The Ang II level exhibits a linear positive correlation to viral load and lung injury, indicating a direct link between tissue ACE2 downregulation with RAS imbalance and the development of organ damage in COVID-19 patients. More studies, however, are needed to confirm this finding.

The potential of ACE2 as a target for COVID-19 therapies

Due to the crucial role ACE2 plays in host cell invasion by SARS-CoV-2, efforts are underway to develop drugs that can block its function in this capacity. To date, no small-molecule drug has been approved via drug repurposing for this application. However, a recently developed biologic drug may achieve this goal. This clinical-grade drug, human recombinant soluble ACE2 (hrsACE2), was originally designed for acute respiratory distress syndrome (ARDS).

The hrsACE2 does not have the membrane-attachment segment and, thus, does not attach to human cells. However, it is capable of binding to the SARS-CoV-2 virus as a decoy receptor. By competitively binding to this coronavirus, it prevents viral binding to the natural, membrane-bound ACE2 and, thus, blocks virus entry into host cells (Figure 4). Studies in cultured cells and various organoids have indeed shown that hrsACE2 inhibited the virus from infecting the host cells. It also appeared to be well tolerated and elicited a rapid decrease in serum Ang II levels in ARDS patients in a 2017 clinical trial. It is hopeful that hrsACE2 may be the first drug that targets ACE2 and will open the door for targeted therapies in the fight against COVID-19. Encouragingly, hrsACE2 has shown potential as a combination treatment, by improving the effectiveness of remdesivir in SARS-CoV-2 infection.

Future therapeutic applications of ACE2

Beyond Covid-19, the ACE2 pathway offers a potential route to treat other respiratory diseases, such as novel 2009 influenza (H1N1) and avian influenza (H5N1), possibly by developing recombinant ACE2 for use along with an AT1R inhibitor or ACE inhibitor. Cardiovascular diseases are another area where ACE2 is of growing interest, and novel targets like ACE2 could help find more effective ways to target the RAS hyperactivity that plays such an important role in conditions like hypertension. ACE2 is also likely to be an important target in the fight against Type 2 diabetes, for example, by using ACE2-mediated pathways to negate the effects of overactive Ang II in the diabetic kidney.

The emerging role of RNA in the development of novel therapeutic treatments is reshaping the landscape of drug discovery, so stay ahead with CAS. Explore our Insight Report on the emerging landscape of RNA therapeutics.

An ongoing theme of the COVID-19 pandemic is the need for widespread availability of accurate and efficient diagnostic testing for detection of SARS-CoV-2 and antiviral antibodies in infected individuals. The ability to detect mild and asymptomatic cases via testing enables early diagnosis and contact tracing, essential steps in preventing the silent spread of the virus. In an effort to meet this need, researchers across the globe are racing to develop highly accurate, efficient, and cost-effective methods for scalable, rapid testing. To assist with better understanding and comparison of the numerous diagnostic tests available, CAS has produced a special report summarizing the basic principles of molecular and serological assays being used in diagnostic tests for SARS-CoV-2. The report highlights recent advancements in testing technologies and provides a high-level view of over 200 diagnostic tests currently available. 

Most tests for early detection of SARS-CoV-2 RNA rely on the reverse transcription-polymerase chain reaction, but isothermal nucleic acid amplification assays, including transcription-mediated amplification and CRISPR-based methodologies, are promising alternatives. Identification of individuals who have developed antibodies to the SARS-CoV-2 virus requires serological tests, including enzyme-linked immunosorbent assay (ELISA) and lateral flow immunoassay. Rapid research is fueling constant improvements in testing accuracy, increased throughput capacity and shorter time to results along with greater variety in point-of-care testing. These advances are critical to enhancing the scalability of testing to meet growing public health demand.  

Ammonium nitrate is a chemical compound with the power to feed billions but also the potential to devastate. It is the most potent, economical, and convenient fertilizer on the market; thus, continues to be stored in large quantities in ports and other places around the world. However, the recent catastrophic explosion in Beirut is a reminder of the hazards associated with the improper storage and handling of ammonium nitrate as well as the need for diligent enforcement of its regulations.

Unless everyone working with ammonium nitrate — manufacturers, sellers, users, first responders, and regulators —  is more aware of the hazards and diligently implements safety rules, then future accidents will be inevitable.

Download this in-depth CAS Insight Report to gain insight into the chemical properties of ammonium nitrate, its hazards and safety rules, and provide a useful resource to key stakeholders within the ammonium nitrate realm.