Recently, the World Health Organization (WHO) classified a new SARS-CoV-2 variant of concern. The new variant, designated Omicron (B.11.539), was first identified by a robust genetic sequencing network in South Africa and reported to the WHO. This unique variant is the most heavily mutated to date, including more than 50 identified mutations, more than 30 of which are on the spike protein. 

Why is the Omicron variant so concerning?

Preliminary study of the Omicron variant indicates that it has evolved significantly from the original version of the virus first identified in China in 2019, which means there is an increased likelihood that it could reinfect those who have already had COVID-19 or evade the immunity generated by the current first generation of vaccines. Such a variant could drastically set back the global pandemic recovery, resulting in staggering societal and economic impacts. 

Its structure is the primary reason the Omicron variant brings about greater concern over immune evasion and transmissibility, even amongst vaccinated individuals. Its multiple receptor-binding domain (RBD) and N-terminal domain (NTD) mutations are associated with resistance to neutralizing antibodies, and protease cleavage mutations are expected to enable easier cell entry or increased transmission. In fact, several studies have shown these mutations affect the immune system's ability to neutralize the mutated SARS-CoV-2 virus and may even reduce immune neutralization tenfold.  

The new variant was originally found in South Africa with cases now identified in Australia, Europe, Canada, Asia, and just recently in the United States. However, many experts believe, based on the previous experience with the spread of the Delta variant, that Omicron has already traveled over much of the globe. Although there have been small molecule drugs, e.g., nafamostat, camostat mesylate, which target non-spike proteins of SARS-CoV-2 and will probably remain effective for Omicron, developing a sustainable vaccine for the current and future variants are crucial for ending this pandemic.

The role of spike protein 

In summary, the SARS-CoV-2 viral spike (S) protein, as shown in the figure below, is the key antigen targeted by the first generation of COVID-19 vaccines, because it enables the SARS-CoV-2 virus to enter human cells. Today’s current mRNA vaccines neutralize the S protein by encoding it as the antigen.

The rapid evolution of the SARS-CoV-2 virus is forcing researchers to assess if the S protein alone is an adequate antigen for vaccine design. With an initial portfolio of vaccines and therapeutics now being deployed to blunt the pandemic, scientists must now consider all that has been learned over the last two years about our immune response to the SARS-CoV-2 virus, what responses correlate with protective immunity, and what relevance these studies have to the construction of second-generation vaccines that potentially will need to expand on or move away from targeting the ever-mutating S protein. 

The path to achieving sustained immunity

Many factors determine how humans develop “protective immunity,” especially against an evolving and mutating virus, like SARS-CoV-2. Ideally, we’d like to achieve an immune response that can recognize and disable things like invading viruses and bacteria. Protective immunity includes both humoral and cellular immunity. Immune responses to SARS-CoV-2 reported in some recently published studies are shown in the table below. Antibody and T-cell responses to COVID-19 proteins in people who survived infection appear broad, but not complete. These responses primarily target virus structural proteins (S, nucleoprotein, membrane protein). A subset of these responses is likely responsible for protective immunity.

*Includes neutralizing antibodies against S protein

The S protein antigen covers the surface of the virus, making it easy for the immune system to find, and an ideal target for protective immunity. However, some humoral and cellular immune responses shown in the table above target SARS-Cov-2 antigens other than the spike protein. These observations, along with the emergence of viral variants and breakthrough infections, suggest that a vaccine focused on immune responses against a single antigen (i.e., the S protein) may not provide the broad immunity needed for an effective vaccine. These types of neutralizing antibodies are often a necessary part of protective immune responses but are not sufficient to establish durable immunity. Whether humoral and cellular responses against other SARS-CoV-2 antigens provide broadly protective immunity needs to be further studied.

What lessons can we learn about achieving sustained immunity from influenza vaccines?

Although we don’t fully understand protective immunity in SARS-CoV-2 infection, recent studies of the influenza virus (IAV) vaccine provide some useful insights. Immunization with the IAV matrix protein (M2e) or nucleoprotein (NP) both produce protective immunity. COVID-19 vaccine researchers could try targeting both the highly variable SARS-CoV-2 S protein and a unique, conserved, SARS-CoV-2 protein, such as ORF8. While the ORF8 protein is currently uncharacterized, it may be a new, conserved antigenic target for second-generation SARS-CoV-2 vaccines. 

A small number of current clinical and preclinical vaccines use whole inactivated virus (IV) or live-attenuated virus (LAV), which should present a broad variety of antigens to the immune system. An even smaller number of multiepitope/multiantigen vaccines are in development and clinical data is lacking. While preliminary suggests that acceptable levels of protection could be achieved, the causes of reduced neutralizing antibodies are not clear and further research is needed to better understand protective immunity. 

An evolving virus requires new treatments

Current vaccines against SARS-CoV-2 that solely target the S protein are an important initial step toward developing antiviral therapeutics and next-generation vaccines. The speed and efficacy with which these were created were unprecedented. Even with new variants like Delta, the data shows that vaccines have drastically reduced hospitalizations and deaths. However, as the virus continues to mutate and evolve, solely targeting the S protein may not be enough for protective immunity. We expect a more comprehensive approach that may include several types of vaccines combined with antiviral therapies that target a broader range of antigens truly stopping the viral spread.

Want to stay up to date on the latest COVID-19 information and resources? Visit our COVID-19 Resources page for unique insights, peer-reviewed publications, and data to accelerate your COVID-19 research. Also, be sure to subscribe to the CAS blog for ongoing updates and insights. 

Masks and personal protection equipment (PPE) have been a divisive topic but are proven to be effective at slowing the spread. Now, with the surge in Omicron BA.5 and BA.2.75 variant infections growing exponentially, improving mask technology will be critical. The COVID pandemic revealed deficiencies in the mask development and production process. However, the innovation of masks will be crucial in slowing the spread of new variants of the virus. 

There are many factors that can be improved for masks, but this article focuses on the emerging science of improving filtration and microorganism removal. 

Rapid Growth in IP and Research 

The CAS Content Collection™ shows that worldwide scholars are focusing on how to make face covers more effective. Over 17,000 documents have been published on face masks, with more than half being from the last two years (Figure 1). Noteworthy is the distinct surge in patent applications, with China, the U.S., and Japan being the leading countries (Table 1). 

Table 1. Distribution of patents related to face masks development among top applicants’ countries

What Are Masks Stopping?

Respiratory droplets are key transmission vehicles for spreading SARS-CoV-2, and those smaller than <5μm are generally categorized as aerosols. Direct exhalation of aerosol particles and droplets from infected patients is the predominant mode of transmission of SARS-CoV-2. Aerosols remain suspended in the air and play a key role in spreading infection. This underscores the importance of limiting aerosol spread, so face masks have been identified as an important tool in pandemic control.

How Masks Work Today

The minimal face mask can include just two layers of household fabrics and is still more effective than not one altogether. Filtration efficiency for particles < 300nm and >300nm can be improved by using different fabrics. This is from the synergistic effect of mechanical filtration from cotton and electrostatic filtration from the other layer comprised of materials like silk (Figure 2A).  

The most used three-layer surgical mask in the COVID-19 pandemic is made up of three layers of nonwoven fabrics (Figure 2B). The three layers of a face mask work together to protect the wearer from harmful airborne particles. The outer layer is waterproof, the middle layer filters out pathogens, and the inner layer traps respiratory droplets. Nonwoven fabrics are cheap and easy to manufacture, which makes them easily accessible to the public.

New Advancements to Improve Masks

New polymeric materials, certain polystyrenes, and polycarbonates have enabled improvements of masks in two areas:  

1.    Better filters: material development to reduce pore size to capture and filter off small particles and pathogens
2.    Better microorganism removal: increased antimicrobial properties through the application of coatings and self-cleaning properties

Improving Filtration 

The efficacy of air filter masks is driven by fiber diameter, membrane thickness, and air permeability. Today's particulate matter filters are made of polymer fibers or fiberglass, which trap particles of various sizes. Recently, new types of smaller membrane filters have been developed that have a larger surface area. These filters are more efficient at capturing particles and reducing air resistance.

Polymer Nanofibrous Membranes

Decreasing fiber diameter to nanoscale leads to enhanced surface area and improved particle removal.  Electrospinning is used for fabricating nanofibrous membranes with good transparency, high efficiency, and low weight. Several types of electrospun nanofiber membranes have been created from different materials. These membranes have different surface properties and can be used for air filtration masks.

Electret Membranes

Due to larger attraction distances, the electrostatic air filters are more effective at trapping particles than the passive membranes. Three charging techniques: in situ charging, corona charging, and tribocharging can be used to fabricate electret membranes. Nanoparticles (such as polytetrafluoroethylene, silicon nitride, magnesium stearate, etc.) are usually employed as charge enhancers. Several hybrid electret filters have been developed via the in situ charging technology of electrospinning. For example, an electrospun polyethylene/polypropylene membrane containing magnesium stearate exhibited a surface potential of 4.78kV and high filtration efficiency of 98.94%.  

A triboelectric nanogenerator has been invented for effective particulate removal by nanofibrous air filters. The triboelectric nanogenerator produces energy from mechanical movements such as human motion and is suitable for use in self-powered wearable devices.  

A self-powered electrostatic adsorption face mask equipped with a triboelectric nanogenerator exhibited highly improved particle removal efficiency. This is another air filter made of multiple layers of nylon and polytetrafluoroethylene fabrics. It is also effective at removing particles from the mask.

Improving Microorganism Removal

While filters capture matter, microorganisms such as bacteria, viruses, and fungi adhere to the filter surface. Therefore, air filters with antimicrobial properties are needed. To date, a variety of antimicrobial agents have been examined to create biocidal properties. These agents include natural products, metal nanoparticles, metal-organic frameworks (MOFs), graphene, and more. 

Certain natural extracts exhibit high antimicrobial activity due to the flavonoids they contain. Natural products like tea tree oils, olive extracts, grapefruit seed, and Sophora flavescens, have been sprayed on the surfaces of fibrous polymeric filters, providing good antimicrobial activity.

New Metallic Applications

Metal nanoparticles exhibit a broad spectrum of antibacterial activities. Their bactericidal action mechanism includes: 

1.    Electrostatic attraction of the positively charged nanoparticles by the negatively charged bacterial cell walls, leading to cell wall disruption and enhanced permeability.
2.    Metal ions can damage cells by causing the production of reactive oxygen species (ROS), which leads to oxidative stress. This disrupts cell functions and eventually kills the cell.

Silver nanoparticles have antimicrobial properties, so they are often used to make masks more effective at preventing the spread of disease. 

Copper and copper oxide both have potent biocidal properties and have been incorporated into textiles and other products with antimicrobial and antiviral properties. The main mechanism of action for copper nanoparticles is the production of ROS during oxidation.

Graphene and its derivatives have been widely explored due to them taking advantage of their large surface area to enhance antimicrobial activity. A recent study reported that graphene-coated surfaces can be used to increase surface temperature and deactivate microorganisms. Upon solar irradiation, rapid local heating is generated and >90% of airborne bacteria are rapidly killed. This way, self-sterilizing reusable graphene masks can be provided.

New Purification Methods

Photocatalytic oxidation air purification is a process that involves a light-activated catalyst reacting with organic pollutants to oxidize them. It degrades diverse air pollutants into non-toxic forms using solar or artificial light. 

Masks including titanium oxide (TiO₂) or zinc oxide (ZnO) nanoparticles have exhibited effective filtration. A mask made of polyester fabric coated with ZnO nanoparticles was found to reduce surface bacteria by 98%.

Multifunctional air filters, which simultaneously remove both particles and microorganisms have proven effective. Recently, an Ag/ZnO nanorod-wrapped PTFE nanofibrous membrane has been created with an outstanding antibacterial activity against Escherichia coli (E.coli).  

Another air filter has been made of carbon nanotubes and silver nanoparticles, with the nanotubes filling the pores of the filter. Loading silver nanoparticles on the high surface area of carbon nanotubes enhances their antimicrobial efficiency.

Metal-Organic Framework Filters

Metal-organic frameworks (MOFs) are porous crystalline materials coordinated to multidentate organic ligands. They are excellent filters because of their high porosity and tunable pore size. 

For example, the incorporation of zeolitic imidazolate framework-8 (ZIF-8) nanocrystals in electrospun polyimide membranes highly enhanced the filtration efficiency of the filters. MOF-based filters can be made on various substrates, such as plastic mesh or nonwoven fabric. These filters work well for particle removal.

Looking Ahead

Masks are an effective way to slow the spread of respiratory viruses like the Omicron BA.5 and BA.2.75 variants. The new technologies and advancements in mask filtration and microorganism removal will be critical to slow future spreads and variants.  

Learn more about COVID-19 variants like BA.5 and how a more comprehensive approach with vaccines, therapies, and masks can help us achieve sustained immunity. 

As COVID-19 cases rise worldwide, the Omicron subvariant BA.5 is now the dominant strain sweeping across the US. The COVID BA.5 variant continues to mutate, increasing its spread and evading immunity. A recent pre-print study shows there are significant health risks with reinfections and new variants may be less affected by therapeutic monoclonal antibodies (mAbs).This blog explores key mutations that increase transmission, evade protective antibodies, and enable more reinfections.

Mutations increase the rate of infection

The spike protein is the key for entry into the human body and has been targeted and neutralized by many of the COVID vaccines. However, recent mutations by the spike protein from the Omicron variants (BA2.12.1, BA.4, and BA.5) suggest critical changes that enhance transmission.   
 

As seen in Figure 1, these three new strains share key mutations that alter part of the receptor binding domain (RBD). This is the part of the spike protein that binds to the cells, enabling infection, and is also a key target for protective antibodies.  

The F486V mutation found in BA.4 and BA.5 compromises the spike’s ability to bind to the viral receptor. The R493Q reversion mutation, however, restores receptor binding and therefore fitness. 

Mutations increase resistance to treatment 

While some mutations enable a faster spread of the virus, others enable the virus to be less affected by current therapies. Mutations to L452 may help the virus bind more closely to cells, hiding from disease fighting antibodies that try to block the virus. Researchers believe that this L452 mutation is the COVID-19 virus’s response to the huge Omicron surges of infection earlier this year. BA.4 and BA.5 also contain a mutation of the N-terminal domain (NTD) domain (Del69-70), which historically has also altered binding affinity, knocking out an antibody binding site. The F486V and R493Q mutations may also contribute to immune evasion from antibody binding, decreasing the efficacy of mAbs and ultimately increasing treatment resistance.  

Bebtelovimab (CAS Registry Number: 2578319-11-4) is the only clinically authorized mAb to treat BA.2.12.1, BA.4, or BA.5 infections that has retained its potency against these newer subvariants. Bebtelovimab is a human immunoglobulin G-1 (variant) monoclonal antibody.

A CAS SciFinder substance search reveals that this therapeutic contains four protein sequences, two identical heavy chain polypeptides composed of 449 amino acids, and two identical light chain polypeptides composed of 215 amino acids. The sequences and modifications can be viewed in CAS SciFinder as shown in Figure 2 and Figure 3.

A recent article in the New England Journal of Medicine shows how the BA.2.12.1, BA.4, and BA.5 subvariants escape neutralizing antibodies induced by both vaccination and infection. They showed neutralizing antibody titers against the BA.4 or BA.5 subvariant and against the BA.2.12.1(lesser extent) subvariant were lower than titers against earlier BA.1 and BA.2 subvariants. These findings provide context for the current surges caused by the BA.2.12.1, BA.4, and BA.5 subvariants in populations with high frequencies of vaccination and previous infection.

Beyond the Spike Protein Mutations 

While BA.4 and BA.5 are identical to each other in terms of spike mutations, they do share and differ in mutations that are outside of the spike protein. These mutations affect viral replication, infection rate, and treatment resistance. Both BA.4 and BA.5 revert two mutations back to the original virus, Orf6 D61 and NSP4 L438.  Researchers believe that these mutations affect replication. Orf6 D61 resident protein Orf6 enhances viral replication by downregulating proteins, enzymes, and various signals. The NSP4 L438 resident protein NSP4 is involved in forming a double membrane vesicle, also potentially enhancing viral replication.  

BA.4 has two mutations, L11F in Orf7B and P151S in the nucleocapsid (N) protein, the impact of which on antigen tests detecting the N protein is not yet established. Both the Orf7B and N protein mutations may contribute to immune evasion. The N protein mutation may also affect the stability of the virus, increasing fitness. BA.5 contains a D3N mutation in the membrane (M) protein - a relatively uncommon mutation. The M protein plays a role in suppression of immunity and also surrounds the virus, increasing possible cell invasion and transmissibility.  

Vaccines proven effective against hospitalization

Current COVID-19 vaccines have minimal protection against symptomatic infections as seen in the data from Minnesota Department of Health, where fully vaccinated individuals are almost as likely to be infected as unvaccinated individuals (figure 4) in June and July when the BA.5 variant was rampant. However, when you examine hospitalization rates, the differences are dramatic as hospitalization numbers are substantially higher in the unvaccinated population (figure 5).   

The current vaccines do offer good protection against severe symptoms, hospitalization, and death. The immunity generated by these vaccines help patients’ immune systems fight the virus and they are therefore less likely to develop severe symptoms and be hospitalized.

An article published in the New England Journal of Medicine discusses how current COVID vaccines are also effective against the BA.1 and BA.2 variants. This cross immunity has been  recognized since the beginning of the pandemic. Evidence suggests influenza, measles, pneumonia and polio vaccines can all offer some level of protection against infection of SARS-CoV-2. According to the Mayo Clinic, people who received a pneumonia vaccine in the past year had a 28% reduced risk of COVID-19, while a 43% reduction in risk of COVID-19 infection was seen in people who received the polio vaccine.

Next Steps: Where do we go from here? 

The COVID-19 pandemic is not slowing down as the virus continues to mutate and evolve across the globe. As shown above, current vaccines are still highly effective against severe disease, hospitalization, and death. However, COVID fatigue has prevented many from receiving their recommended booster vaccines. If an individual is eligible but has yet to receive a booster vaccine, they should receive one as quickly as possible. Renewed efforts to wear a high-quality mask when in confined, crowded environments will also help curb symptomatic infections.    

Both Pfizer and Moderna have developed vaccines based on the new BA.1 variant that should be available in the US during the 2022 fall season. The limited protection that prior BA.1 infection provides against the newer variants raises questions about how useful this type of second- generation vaccine will be though. In the future, newer vaccine technologies combined with antiviral therapies that target a broader range of antigens will be required to stop the viral spread.   

COVID-19, the disease caused by the novel coronavirus SARS-CoV-2, has infected several million people and resulted in hundreds of thousands of deaths worldwide.  Although remdesivir and favipiravir have been conditionally approved to treat COVID-19, as the case count continues to climb daily, additional COVID-19 therapeutics are still desperately needed to mitigate the myriad symptoms and long-term damage COVID-19 is causing patients. 

Bioassay data points the way to promising drug candidates 

In support of ongoing research efforts to identify additional drugs for COVID-19, a team of CAS scientists analyzed published scientific information and created a comprehensive report focusing on proteins involved in COVID-19 and potential corresponding drug candidates. This report was recently published in ACS Pharmacology & Translational Science.

Read the full open-access article for a comprehensive listing of COVID-19 protein targets and associated drug candidates as well as related bioassay data.

A large number of substances targeting proteins that are critical to SARS-CoV-2 infection were identified, and relevant published bioassay data were analyzed. Figure 1 shows the number of substances for each specific protein involved in SARS-CoV-2 and related viral infections. Given the demonstrated activities and the similarities of these proteins between SARS-CoV-2 and related viruses, these substances warrant further investigation for drug development against COVID-19.

Crucial connections between proteins and drugs

Developing effective drugs for any disease usually requires developing a detailed understanding of protein-drug interactions.  On one side of this equation lie protein targets, also called drug targets, which are proteins that play important roles in the progression of a disease. Identification and validation of protein targets is the first step of the drug discovery process, and such work often comes from basic research on the mechanisms of disease development.  On the other side are drug candidates. The pharmacological properties of a drug candidate against its specific protein target can be measured by bioassays that assess the biological effects of the drug candidate at various concentrations. Typically, bioassays include measurements of the binding of a drug candidate to the protein target, the level of inhibition of the protein’s activity, and the level of the physiological response due to such inhibition. 

Key proteins involved in COVID-19 and potential drug candidates

Since the emergence of COVID-19, researchers have already identified many of the viral and human proteins involved in the SARS-CoV-2 infection process. All of these are potential drug targets, but here we will highlight eight that are of high interest. These include five viral proteins (spike (S) protein, 3CLpro, PLpro, helicase and RNA polymerase (RdRp)) and three human proteins (ACE2, TMPRSS2, and furin), that play roles either in mediating viral entry into host cells or in the viral replication cycle inside host cells. These proteins are illustrated in Figure 2, and their functions in the infection process are discussed in the table below. Also shown in the table are some examples of compounds that inhibit these proteins and thus are under consideration as potential COVID-19 therapeutics.  

As part of the global scientific community, CAS has committed to leveraging all of our assets and capabilities to support the fight against COVID-19. Explore the additional CAS COVID-19 resources including scientific insights, open access compounds and SAR datasets, and special reports. 

Artificial intelligence. Machine learning. Big data. Within the next decade 70% of large companies will attempt enterprise digital transformation, but only 30% will succeed*.

How do you get past the AI hype and begin accelerating discovery in a digitalized world? Pave a clear path forward for data and digital transformation success with knowledge from CAS digitalization experts. CAS data analysis specialists have modeled custom data sets for decades using human intelligence to navigate the IP and patent landscape and provide business intelligence. Our predictive analytics and chemical R&D technology solutions speak for themselves.

This CAS Insights Report provides several case studies to demonstrate the challenges and opportunities in building a successful digital transformation framework with actionable AI analytics.

Artificial Intelligence: Big business

The artificial Intelligence (AI) industry is at the forefront of digital technologies and is transforming business to the extent that by 2023, it will have an estimated value of half a trillion USD. However, its advancement often raises a polarizing debate: That of man vs machine. Could robots push people out of jobs and take over our world?

According to an IDC report, worldwide spending in the AI market is set to grow 19.6% year-over-year in 2022 to $432.8 billion, leaving it on its way to breaching the $500 billion mark by 2023. IDC expects AI services to see the fastest spending growth at a compound annual growth rate (CAGR) of 22%, with AI platforms showing the biggest growth (34.6% CAGR) out of all AI software surveyed.

The AI drug development process

As standard, it now takes an average of 10–15 years for a drug to be identified, validated, developed and approved for clinical use. There are multiple challenges that come with bringing a new drug to market, the most notable being cost, which is estimated at $2.6bn with an approval rate of only 12%.

Drug discovery reinvented with AI

When it comes to digitalization, the pharmaceutical industry is at the forefront of cutting-edge research, capitalizing on the advancements that come with AI drug design. AI can recognize hit and lead compounds and can rapidly validate drug targets while also optimizing drug structure design.

Certain AI algorithms (e.g., Nearest-Neighbor classifiers, Radio Frequency (RF), extreme learning machines, Support-vector machines (SVMs), and deep neural networks) are used for virtual drug screening based on synthesis feasibility and can predict the physicochemical properties, bioactivity, and toxicity of target molecules, devoid of bias.

AI drug design can assist in structure-based discovery by predicting the 3D protein structure and providing vital information on the effect and safety of a compound prior to synthesis. AI methods have also been used to accurately predict ligand–protein interactions — ultimately ensuring better therapeutic efficacy. Prediction of drug–target interactions with AI has also been employed for drug repurposing and avoiding polypharmacology, which may relay substantial cost savings.

The involvement of AI in the de novo design of molecules can be beneficial due to its ability to provide online learning and simultaneous optimization of the already-learned data, as well as suggesting possible synthesis routes for compounds leading to swift lead design and development.

Finally, AI-enabled search solutions can play an important role across the entire patent ecosystem in improving both efficiency and patent quality. They can perform and review complex prior art searches, freeing time for patent examiners to undertake other tasks and reduce application delays.

Man and machine: Living in harmony?

Despite the myriad of applications in the AI drug development process, there are drawbacks to using AI in drug discovery, and human intervention will continue to be essential to the process. The quality of the predictions generated are largely dependent on the algorithm design. AI is also subject to algorithm bias, and algorithms must still be validated by scientists. While costs of supercomputing and high-throughput screening have decreased over time, they remain substantial.

One potential solution to such challenges is human-in-the-loop (HITL) AI, which combines the efficiency of AI and robotics with researchers’ input, ideas, and comprehensive judgement — saving time and resources while minimizing failures. This approach has been employed by Astellas, where one HITL method was proven to reduce the time from hit compound to acquisition of a drug candidate compound by approximately 70%. CAS has evaluated the structural novelty of the first three AI-designed drug candidates to enter human clinical trials. The first drug candidate, DSP-1181, was reported by Exscientia in early 2020. Two drug candidates — EXS21546 and DSP-0038 — have since followed suit with a pipeline of others rapidly progressing towards this milestone as several companies, including Exscientia, Insilico Medicine, and Schrodinger, are conducting preclinical, Investigational New Drug-enabling studies on potential candidates.

One cannot argue the benefits that AI drug development can bring to optimizing therapeutic discovery: AI can be harnessed to push the boundaries of technology when paired with innovative scientific thinking. Read more on this topic in our CAS Insights Report on the landscape of AI and chemistry.

Created through the US FDA Safety and Innovation Act of 2012, Breakthrough Therapy Designation (BTD) was introduced to shorten the development and review time of promising new drugs intended to treat serious or life-threatening diseases for which there is an unmet medical need. The Breakthrough Therapy Designation approval pathway is distinct from other expedited development programs in that greater evidence of efficacy is required, but in return, sponsors receive much more substantive engagement and support from the FDA during clinical development. A key requirement for receiving Breakthrough Therapy Designation status is preliminary clinical evidence demonstrating substantial improvement on a clinically significant endpoint compared with other available therapies. Once designated as breakthrough therapies, investigational drugs receive intensive FDA guidance on an efficient drug development program, an organizational commitment to expedite the FDA development and review, and the potential eligibility, based on supporting clinical data, for rolling and priority review of the marketing application.    

Receiving Breakthrough Therapy Designation status is considered a major accomplishment for any pharmaceutical R&D organization, bringing with it both public health and commercial benefits. Data shows that in addition to review periods being shortened, Breakthrough Therapy drugs will also spend a total of two to three years less in pre-market development compared with non-breakthrough therapy drugs. Furthermore, receiving this designation provides some credibility to the clinical promise of a given product and, as a result, can add significant value to a company. In fact, our analysis of publicly announced Breakthrough Therapy Designation grants found that the stock of publicly traded companies without any marketed products rose by an average of 6% (in excess of market returns) the day after Breakthrough Therapy Designation was announced. 

The connection between chemical novelty and Breakthrough Therapy Designation

With such significant benefits, breakthrough therapy status remains a coveted but elusive prize. As of June 30, 2022, the FDAhad received 1265 total requests for Breakthrough Therapy Designation. However, only around 40% of these requests were granted.

The breakthrough status for a given drug is not disclosed by the FDA until it receives final approval. Between 2013 and 2019, just 73 (26%) of the 276 new therapeutic drugs (NTDs) approved by the FDA's Center for Drug Evaluation and Research (CDER) were granted BTD status. Small molecules were the dominant drug modality, representing 56% of these breakthrough NTDs. A majority of these FDA-designated breakthrough small molecule drugs included at least one structurally novel new molecular entity (NME) whose shape and scaffold were not used in any previously FDA-approved drugs. However, a closer look at the success rates for different types of small molecule drugs reveals some interesting findings.

Based on our recent analysis, approximately 3 in 10 structurally novel small molecule NTDs achieved breakthrough status compared with just 1 in 10 non-structurally novel small molecule NTDs. That means structurally novel drugs have been more than twice as likely to be granted Breakthrough Therapy designation status by the FDA. This gap highlights the differential impact of structural novelty and the importance of pushing the boundaries of chemical space even further in the search for new drugs.

In silico methods accelerating small-molecule drug innovation 

Balancing innovation with efficiency is a longstanding challenge in drug discovery, as the pharmaceutical industry is under constant pressure to develop novel therapies that have significant clinical advantages over existing treatments. Structurally novel molecules have proven to be significantly more likely to be the source of promising new therapies. However, with the number of potentially synthesizable organic molecules estimated to be 10180 for those below 1000 Da, the exploration of the vast amount of chemical space in search of structurally novel drugs is beyond the reach of traditional experimental approaches.  

Advancement of in silico methods is beginning to drive more efficient exploration of new biologically relevant regions of chemical space that contain structurally novel molecules. One of the primary in silico methods that many biopharma organizations have attempted to deploy over the last several years is machine learning. Machine learning can be used to predict the properties of a drug moleculewith an increasing degree of accuracy. This insight helps researchers prioritize the synthesis of drug-like molecules with more optimal property profiles and allows for the creation of more structurally diverse candidate pools of molecules representing larger portions of chemical space. These structurally diverse pools increase the odds of finding structurally novel drug-like molecules by providing a better selection of molecules that could be synthesized and assayed.

Advancing machine learning effectiveness in drug discovery

When it comes to building powerful predictive algorithms to explore chemical space broadly for drug discovery, the use of high-quality training data is key. Machine learning methods may draw on a range of different sources of public and internal, proprietary data.  However, this disparate data must be refined, translated, structured, and indexed to unlock its true value. In fact, data scientists are still spending 38% of their time sourcing and cleaning up the data used to feed their algorithms – time that could be more productively spent developing models and optimizing results. Thus, the availability of data sets that are curated by human experts with experience in taxonomies, semantic linking, and data categorization can have a significant impact on the success of machine learning efforts in drug discovery.

Equally important are the molecular representations or ‘molecular fingerprints’ that are used to encode the structure of drug molecules in a form that is amenable to machine learning. Recent research showed that optimized fingerprints can make a significant difference in the accuracy of predictive models. Indeed, a new molecular fingerprint developed by data scientists at CAS improved prediction accuracy by up to 45% compared with the same algorithms running traditional Morgan fingerprint methods. These enhanced molecular fingerprints are already showing great promise in our drug discovery consulting projects to predict the biological activity of drug-like molecules, thereby helping to reduce the number of molecules that must be synthesized for screening and increase research efficiency in the search for the next generation of innovative therapeutics.

Interested in analyzing the structural novelty of your own intellectual property or optimizing your digital R&D initiatives? CAS Custom Services tailors our specialized technologies, scientific expertise, and unparalleled content to meet your unique needs.

How can CAS close knowledge gaps on emerging trends?

Stay on top of emerging approaches within drug discovery with CAS. Beyond structural novelty, small molecules are being used to find novel modes of targeted undruggable proteins. This has created new classes of therapeutic agents with exciting potential activity for many therapeutic areas. Learn more about the molecule glues drug discovery landscape, targeted protein degradation, and induced proximity in our latest white paper. 

The mRNA vaccine success story

Messenger RNA (mRNA) vaccines are a familiar concept to many, owing to their role in substantially altering the course of the COVID-19 pandemic and preventing millions of deaths. However, they are not a novel discovery. In fact, the therapeutic potential of mRNA can be linked back to the 1980s when it was hypothesized that mRNA could be used as a drug when delivered to a target via lipid droplets. Since then, mRNA vaccines have been designed to target an array of pathogens, including zika, rabies, influenza, and cytomegalovirus. Figure 1 below outlines the mechanism of action of mRNA vaccines for inducing cell- and antibody-mediated immunity.

In contrast to conventional vaccine approaches, which directly introduce antigenic proteins that stimulate an immune response in the host, mRNA vaccines introduce mRNA encoding to a disease-specific antigen and leverage the host cells’ protein synthesis machinery to produce antigens that elicit an immune response. The production of these foreign antigens within the body prepares the immune system to recognize and memorize this viral antigen so it is ready to fight off future infections caused by a virus with the same antigen.

Watch this video to see how an mRNA vaccine uses our bodies’ cells to generate immunity to COVID-19. 

mRNA vaccine: the long and winding road

The successful application of mRNA vaccine technology to combat COVID-19 would not have been possible without the pioneering work of biochemists, immunologists, and developmental biologists. But the road to success has been long and winding, with decades of dead ends and disputes over technology. Researchers initially found mRNA technology a struggle to work with due to its instability: a challenge that was largely overcome with the development of lipid nanoparticles (LNPs). Encapsulating mRNAs within these protective little fat bubbles enables them to be shuttled to the right place in cells without degrading.

While initial studies into mRNA vaccines looked promising, the cost of optimizing and upscaling vaccine platforms was a major limiting factor to large-scale rollout. Early attempts to develop and commercialize mRNA vaccines were abandoned due to manufacturing challenges, including a vaccine for avian influenza. Many of the candidate vaccines never progressed to in-human studies, and companies such as Shire and Novartis sold their mRNA vaccine portfolios. Companies could not see the economic potential in the technology. 

Rise of the COVID-19 mRNA vaccine

The COVID-19 pandemic had a big impact on vaccine development. Suddenly, mRNA was rapidly and successfully deployed as a vaccine to treat the novel coronavirus, SARS-CoV-2. Through a coordinated research effort, two mRNA vaccine candidates were quickly awarded emergency approval to fight COVID-19. These vaccines offered several advantages over conventional vaccines, including:

• Increased specificity and efficacy resulting from induction of both B- and T-cell immune responses.
• Ease of production in large quantities in a cell‐free environment by in vitro transcription (IVT), which allows for faster development, a simplified production process, and more cost-effective manufacturing

• Safety advantages, namely the absence of integration into the host cell genome and no DNA interaction (thus, no mutational risk to the host), no viral particle formation, and transient antigen expression (limiting its persistence in the body).

The concerted efforts of scientists around the globe during the COVID-19 pandemic has accelerated mRNA vaccine development and helped us to overcome the challenges that hindered early research. The knowledge garnered from the pandemic will be valuable to the field of vaccine technology and the quest in producing future vaccine design using RNA approaches.

The mRNA vaccine pipeline

Bolstered by the success of the COVID-19 mRNA vaccines, around 90 lead developers are developing mRNA vaccine candidates for a vast array of pathogens. Moderna alone is developing mRNA vaccines to combat Epstein-Barr virus, cytomegalovirus, seasonal flu, and respiratory syncytial virus. Plans to develop mRNA vaccines for Herpes simplex virus, multiple sclerosis, cancer, and human immunodeficiency virus are also in the works. Clinical trials on the first mRNA-based malaria vaccine are set to start this year, with the hopes of tackling this long-neglected disease. The applications of this technology are seemingly limitless.

A glimpse into the pipeline shows that researchers are exploring a range of mRNA technology formats, including modified, non-modified, and self-amplifying mRNAs. While LNP formulation remains the most popular approach for delivering the mRNA to its target, alternative delivery vehicles, such as cationic nano-emulsions, and polymers, are also being explored. Developers believe that these new formulations may bring advantages in stability, potency, immunogenicity, and valency. However, with approximately three-quarters of mRNA vaccine candidates in the preclinical/exploratory phase of development, it will be several years before we see how these new technologies fare in clinical trials. 

Optimizing mRNA vaccines for future use

Though the field of mRNA vaccines has advanced in recent years, several process development challenges remain, such as Plasmid DNA supply, the complexity of in vitro transcription and encapsulation processes, varying mRNA impurity profiles, and the need for ultra-cold storage.

There are other factors that reinforce the need for continued innovation, such as the risk of potential emergence of viral variants (as seen with COVID-19) and the need for high dose administration and subsequent injection site reactions in individuals being vaccinated against SARS-CoV-2. 

Stability

Despite being an important attribute, minimal research has been performed investigating the stability profile of mRNA drug products, e.g., LNP-mRNA and protein mRNA complexes. include several that investigate the effects of freeze-drying on mRNA integrity. Other approaches include spray-drying mRNA and generating LyoSpheres (freeze-dried droplets with mRNA). This area of research will be crucial for large-scale mRNA vaccine deployment in the future.

Cost

As aforementioned, cost was a key limitation to the advancement of mRNA vaccines in the early days, and this is set to remain an important consideration. Currently, relatively high amounts of RNA are required to produce a vaccine, which not only costs time and money, but also increases the likelihood of potential side effects (more on this shortly). Furthermore, the ultra-low temperature storage of -70°C is costly, requiring special freezers that may not be normally present at distribution or vaccination centers. Researchers predict that investments in the manufacturing infrastructure and raw materials required for mRNA vaccines will also lower the cost of these vaccines in due time.

Lowering the dose

One way to navigate the challenges of RNA dose lowering is by using self-amplifying RNA. 
It is similar to RNA in terms of structure, but much larger, encoding a replicase that enables amplification of the original stand of RNA upon delivery into the cell. The result is a much higher yield of protein requiring a minimal dose of RNA, leading to additional cost and efficiency benefits. However, one potential issue is the size of the molecule and the impact of this on delivery.

mRNA vaccines have been in use for years, but their clinical potential remained untapped until the advent of a global pandemic. Substantial progress has been made in the space of a few years. The priorities are clear in terms of what’s required to produce a new generation of mRNA vaccines. Watch this space for new developments. 

A therapeutic world beyond mRNA vaccines

To uncover the world of RNA-derived therapeutics beyond mRNA vaccines, see our insights report “RNA-Derived Medicines: A review of the research trends and developments”, on the application of RNA in medicine and how chemical modifications and nanotechnology can enhance the delivery and efficacy of RNA pharmaceuticals.

With rising sea levels and climate change impacting communities across the globe, industrial nations are looking to manage output and identify processes to reduce their impact on the environment. One approach that has gained momentum since the 1990s is green chemistry, a scientific field focused on "the invention, design, and application of chemical products and processes to reduce or eliminate the use and generation of hazardous substances."

In 1998, Paul Anastas and John Warner co-authored a book setting out the 12 principles that form the basis of green chemistry, including a range of ways to reduce the environmental and human impact of chemical production. However, in some industries the adoption of green chemistry practices is seen as an unjustified compromise to profitability.

Making waves in the pharma industry with green chemistry

According to the ACS Green Chemistry Institute, "After all of the research advancements in green chemistry and engineering, mainstream chemical businesses have not yet fully embraced the technology. Today, more than 98% of all organic chemicals are still derived from petroleum." As the green chemistry movement continues to influence policy, business practices and consumer perception, companies must find new ways to "go green" while maintaining their bottom line. This is particularly true in the pharmaceutical industry.

The ACS Green Chemistry Institute has formed the ACS GCI Pharmaceutical Roundtable to "encourage innovation while catalyzing the integration of green chemistry and green engineering in the pharmaceutical industry." Members of the Roundtable include AstraZeneca, Bayer, Lilly, GlaxoSmithKline, Merck & Co., Novartis, Pfizer, and Takeda, among others

The involvement of so many well-known pharmaceutical companies is encouraging, as the industry has historically been resistant to altering proven manufacturing and research methods. Although the adoption of green chemistry principles could be viewed as an additional hurdle for an industry already challenged with regulatory issues, intellectual property demands, and fail fast requirements, pharma companies are beginning to realize the efficiencies and cost savings it offers.

By applying the atom economy principle of green chemistry(i.e., synthetic methods should be designed to maximize the incorporation of all materials used in the process into the final product) in pharma R&D, fewer byproducts are produced, thus minimizing storage and disposal costs. Solvents can also significantly impact costs, as they typically account for 50-80 percent of the mass in a standard batch chemical operation, drive most of the energy consumption, and cause the greatest concern with process safety.

For example, Merck developed a greener way to make molnupiravir, an antiviral medicine for the treatment of COVID-19. Benefits included reducing solvent waste, increasing yield by1.6 fold, and cutting a five step process down to three. In 2022, The U.S. Environmental protection Agency recognized the work with the Greener Reaction Conditions Award.

Amgen developed a greener synthesis for LUMAKRAS™, a novel drug for the treatment of certain non-small cell lung cancers. Benefits included cutting a purification step that generated large amounts of solvent waste, saving £3.17M per year, and boosting yield. In 2022, the U.S. Environmental Protection Agency also recognized the work with the Greener Reactions Condition Award.

Staying ahead of the green chemistry curve

At the heart of every pharma company is the promise to deliver groundbreaking drugs to improve lives across the globe. To achieve this goal in a sustainable, environmentally friendly way, pharma companies require access to the latest research in the field. They must innovate beyond traditional synthetic processes.

Starting in the late 1990s, and coinciding with publication of the groundbreaking book by Anastas and Warner, there has been a dramatic increase in research related to the scope of green chemistry in the design and synthesis of pharmaceutical agents. Today, the scientific literature includes more than 2.1 million journal articles related to the field.

As with many emerging fields, the use of inconsistent terminology in the scientific literature presents a challenge to those looking to leverage the latest findings. Pharma companies need information solutions that enable their researchers to easily locate greener chemistry: reactions, reagents, solvents, and catalysts as they optimize their syntheses for sustainability.

At CAS, our scientists index green chemistry-related information as they curate the world's largest collection of chemistry insights. This intellectual indexing allows pharma researchers to quickly track down the green chemistry information they need, including more than 45 thousand "green" chemical reactions from the unparalleled CAS Content Collection™. 

CAS also provides landscape views on the latest green chemistry trends that can impact other aspects of manufacturing including packaging development. Learn more in the CAS Insight Report exploring “Bio-based Polymers: A Green Alternative to Traditional Plastics”.