Core Concepts
In this article, you will learn about various strategies for discovering new biopharmaceutical drugs, and how drug discovery fits into the greater drug development process. Given this context, you will explore how researchers employed the drug discovery process to conceptualize COVID-19 treatments in particular.
This is the second article in a special ChemTalk mini-series about the intersections between chemistry and public health, using COVID-19 as a case study. Across this series, you can expect to learn about the drug discovery and development processes, chemistry’s central role in diagnosing and preventing diseases, and careers that are on the front line of chemistry and public health.
Previous Articles in This Mini-Series
> The Chemistry Behind Coronaviruses
What is the drug discovery process?
Think back to the last time you used a medication. Maybe it was anesthesia, soothing you to sleep before a surgery and keeping you unconscious throughout. Or perhaps it was the help of an antibiotic that cleared up your strep throat or swimmer’s ear in no time. Or, with the change of seasons, you find yourself shopping for antihistamines to ease your allergy symptoms.
Medicinal drugs come in all forms. But where do new medicines come from? It all begins with the trial and error of the drug discovery process, which is how chemists and biomedical researchers identify compounds that could potentially serve as pharmaceutical drugs. Subsequent studies help to assess how the compound works and whether it would make an effective medication.
Before we examine how drug discovery works, let’s spell out the differences between it and the closely-related drug development process.
Drug Discovery vs. Drug Development
The drug discovery and drug development processes are separate, yet intertwined with and dependent upon each other. Both must happen before patients can receive the drug they need. Let’s consider some core distinctions between these processes.
Drug Discovery in Detail
Drug discovery is always the first step, rooted in inquiry and exploration. Sometimes biomedical researchers use an intentional approach and search for areas of unmet need (conditions without any suitable drug treatments). Patients affected by these conditions would arguably benefit the most from a new drug. Other times, a drug already exists for a specific condition, but that drug has a downside like unwanted side effects. In this situation, it might be worth pursuing a better drug for that condition, so those patients have additional treatments. Alternatively, after a drug’s patent has expired, different biopharmaceutical companies can manufacture drugs with the same active ingredient. Manufavturers will market these products under unique brand names, though the formula behind them is similar.
Scientists may even discover compounds by accident, then continue studying it to decide if it will make a useful drug. But these research efforts engage more than just the immediate researchers. These studies can’t be done without the participation of a vast range of biopharmaceutical experts, medicinal and synthetic chemists, regulatory authorities, health care professionals, even animals and computers and robots!
Even if a condition already has viable drugs, it can be helpful to work toward more treatment options. Suppose that a patient is allergic to the active ingredient in the main drug for their condition. Wouldn’t it be ideal to have other drugs available which use different ingredients? Or, a particular brand of medication may be prohibitively expensive. When this happens, having other brands or the generic version of that drug on the market could make the medication more accessible and affordable for patients.
And let’s not forget that, in the background of all this pharmaceutical action, non-biomedical treatments can support patients too. Depending on the condition, successful treatments might involve lifestyle changes, alternative or holistic approaches, and the surprisingly powerful placebo effect. The difference lies in how these treatments are brought to the patient. Biomedical treatments like pharmaceutical drugs must face strict regulatory specifications before use regarding safety, efficacy, and quality, whereas other treatment types may not.
An Introduction to Drug Development
Once a compound shows medicinal promise, biomedical researchers launch the drug development process, rooted in investigation and active research. Scientists further evaluate and refine the most promising candidate compounds from the drug discovery process. They’re looking for details about the proper dosage to use, how the body metabolizes the compound, how the compound interacts with other medications, how it compares with existing drugs for the same condition, and more.
In the U.S., scientists must test all investigational new drugs (INDs)—new drugs, and approved drugs being repurposed to treat new conditions—on animals before humans. Research tools like cell culture and computer models can substitute animals to an extent, but some amount of animal testing is necessary to bring an IND to market. Out of these tools, animal models most accurately demonstrate how drugs behave and interact in living systems. Technology can’t fully replicate physiology, so animals make valuable contributions to biomedical research. Complex organisms typically represent humans best, but due to ethical concerns, researchers limit animal testing when possible or use simpler organisms if appropriate. For example, studying genetic disorders could begin with Drosophila fruit flies, then rodents like mice or rats, and even highly-complex animals like primates. When animal testing must happen, it’s taken very seriously, and regulations ensure the animals have ongoing care and enrichment.
It can take years, sometimes more than a decade, to fulfill the combined drug discovery and development processes. As we’ll cover in an upcoming article, the later stages of drug development requires in-depth clinical trials and follow-up studies. Regulatory agencies, like the Food and Drug Administration (FDA) in the United States, oversee these trials and provide approval if they deem the drug safe and effective. Only after this approval can patients use the drug. However, it’s worth noting that individual countries have their own regulatory agencies, so even if a drug is approved in one country, it may not be available to patients elsewhere. It takes extra time—not to mention additional studies—to market a drug internationally.
Due to these rigorous standards, only a slim percentage of drug candidates get approved and ultimately make it to market. Though this procedure may seem extensive, it’s necessary for evaluating whether the drug is working as intended, determining if there are any unpleasant side effects, and monitoring patients’ short- and long-term well-being. These research areas also help scientists understand how to improve the drug, in an effort to make patient outcomes as successful as possible.
How does the drug discovery process work?
Imagine this: you’re a biomedical researcher tasked with inventing the next innovative, exceptional medication. Unless you encounter a candidate compound by accident or sheer luck, this process will take some deliberate planning. What is the condition you want to treat? Is your goal to cure the condition, or simply to alleviate symptoms? Will your drug have a narrow scope and treat only one condition, or could you design it to tackle multiple similar conditions?
Drug discovery is a complex, often collaborative endeavor that may feel like looking for a needle in a haystack. Sometimes researchers invest countless hours and jaw-dropping amounts of money in a candidate compound, only for that compound to later prove unsuccessful as a drug. It’s all part of the journey, and it’s all worth it when a patient finally gets the safe, effective medication they’ve been waiting for.
The Search is On: Drug Discovery Strategies
Given that there is a lot of uncertainty during drug discovery, it can be intimidating to navigate. But it doesn’t have to be. Over the next few sections, we’ll look at some of the major milestones in the drug discovery process. As we do, keep in mind that, since drug discovery can happen in a myriad of different ways, not all candidate compounds undergo the same exact steps.
Bullseye! Pinpointing Biological Targets
Did you decide which condition you plan to make a drug for? At this point, it’s very helpful to know the basics of how that condition works in a patient who has it. This background knowledge of the condition’s pathophysiology will inform and shape your first steps drug discovery steps.
For example, let’s say you want to make a pharmaceutical cancer treatment. There are many different types of cancers, but the common thread underlying all of them is that cancerous cells divide in an unregulated way. All cells have p53, a protein that modulates cell division. Sometimes, cancerous cells have mutations in the p53 protein, so the cell divides uncontrollably.
This inspires cancer researchers to design drugs that act on the dysfunctional p53 protein. Here, p53 is the drug’s target, the molecule that the drug binds to in order to change the molecule’s function. Depending on the condition being treated, the drug’s target may be a protein (like p53), a nucleic acid, an antibody, a gene, or some other molecule. The target’s characteristics and function will serve as the framework for later drug development, when the scientists will design and create a drug to interact with the target. Remember, the pathophysiology of a disease includes elements from the entire cell cycle, from activating or deactivating DNA transcription and translation, to the chemical processes that involve proteins of interest.
To maximize safety and minimize negative side effects, drugs need to be as precise as possible. Drugs are precise when they act only on the target or targets they’re designed for, without acting on any other compounds. Usually, a drug is meant to have one, and only one, target. In other words, the drug will only interact with one specific molecule in the patient’s body. But if a drug has multiple targets, the drug could have some unintended side interactions, or off-target effects. Drugs with multiple targets are said to have drug promiscuity. Since off-target effects could be unpleasant side effects, it’s important to evaluate off-target effects in the context of patient safety. Every patient is different, and a drug that works in one patient’s body may not work well in another’s.
Drug precision is how scientists customize drugs to target a specific compound and, as a result, treat a specific condition. Let’s briefly return to our example from before. It goes without saying that cancer patients should receive pharmaceutical drugs that treat cancer. Administering a drug for another condition instead would likely be useless in treating cancer, or it might even cause unpleasant side effects for the patient. Imagine if you went to the doctor seeking relief for a bacterial sinus infection. How would you feel if the doctor prescribed you an antifungal drug instead? It would be fine if you also happen to have a nasty case of athlete’s foot… but otherwise, that drug wouldn’t help you get better. An antifungal drug won’t target the bacteria causing your sinus infection.
So, it might be beneficial to give a cancer patient a drug that targets mutated p53. This drug would intervene with the uncontrollable cell division, maybe by regulating the cell cycle or by deactivating the mutated p53. But if this drug acts on cellular proteins in addition to p53, this could lead to disastrous effects on the cell’s structures or function. Potentially, using this drug could lead to a worse outcome than using no treatment at all. This is why minimizing off-target effects and tailoring drugs to be highly specific go a long way in keeping people safe.
Regardless, not all off-target effects are harmful. Sometimes side effects happen, but are harmless. Some may even be positive, if the off-target effect ends up reducing the symptoms of another condition the patient has. Through polypharmacology, pharmaceutical scientists purposely design a drug to have multiple targets, in an attempt to treat multiple conditions. For example, bispecific drugs have two separate binding domains, so the drug binds to two targets simultaneously.
So, instead of being a discouraging obstacle in the drug discovery process, off-target effects may present a new opportunity. They might even push the drug discovery process in an entirely new direction. Midostaurin, for instance, was designed as a protein kinase C inhibitor, allowing it to inhibit cancer cell proliferation. As time went on, researchers found that midostaurin also has an off-target effect on other kinds of kinases. Inspired by the possibility of using midostaurin to treat conditions besides cancer, the researchers then studied its ability to inhibit other kinases. Notably, they studied midostaurin’s impact on vascular endothelial growth factor receptor kinase, which regulates angiogenesis (blood vessel formation), to treat patients with diabetic retinopathy (damage to the retina’s vessels caused by high blood sugar).
Compound Screening
You have a condition in mind. You have a target molecule you plan to act on. And you have a lot of patience and persistence. Now, you’re ready to move on to the next step: compound screening.
Compound screening is a massive undertaking where scientists search for compounds that interact with the target molecule. There are several different ways to execute this search, and scientists can use multiple ways to get a well-rounded understanding of how the target molecule behaves in context. Old-fashioned techniques like pouring over the scientific literature can be a great start. But nowadays, computers often streamline screening by offering databases of compounds that are pertinent to the condition or the target.
High-Throughput Screening
Two common methodologies guide the compound screening process. High-throughput screening (HTS) uses automated tools, like robotic lab equipment, to screen lots of compounds—even millions of them. Considering the sheer quantity of compounds the researchers must screen, HTS assesses these compounds’ interactions and characterizes their biochemical properties very efficiently. There are two main components to HTS, data collection and data processing, and HTS automates both.
During data collection, a robot or similar instrument tests many candidate compounds for the chemical reactions scientists are looking for. For instance, promising compounds might undergo fluorescence, scatter light, or undergo color changes. Compounds that react in a desirable way might warrant further study in future stages of the drug discovery process. The robot can perform steps that a human researcher would typically do: mixing reagents, transferring liquids, incubating test articles, and more. Using a robot for these tasks ensures that they’re always performed quickly and consistently, maximizing quality control and freeing up researchers’ time to conduct other experiments.
During data processing, the researchers put the robot’s test results into context. Testing so many compounds in a short period time means that there are a lot of results to process. Luckily, this is somewhat automated too. Modern research software can often automatically perform calculations, making it easier for scientists to draw conclusions about large data sets. Or, if several robotic instruments are working in tandem with one another, it may be possible for the instruments to communicate their results to one another. When it comes time to analyze the results, this puts all of the robots’ data in one place so the scientists can readily integrate different data sets together.
High-Content Screening
The complementary strategy of high-content screening (HCS) combines cell biology and pharmacology to see how a candidate compound alters cells. Identifying direct connections between candidate compounds and their effects shows which compounds could best intervene in the disease pathway. In HCS, researchers utilize fluorescent labels to visualize relevant information about the candidate compound. Fluorescent labels are molecules that tag other molecules or cellular structures of interest, and appear bright and often colorful.
Fluorescent labeling is a common biochemical process with many laboratory applications. For the drug discovery process, researchers label cells with a fluorescent tag that’s selective for cellular structures or molecules of interest. Then, through HCS, they treat the labeled cells with individual candidate compounds. After a compound has interacted with the cells, the researchers look at the cells under a fluorescent detector or microscope. This equipment picks up on the fluorescent label, so it visualizes changes in the structure or molecule of interest. Has the candidate compound destroyed a cellular structure? Altered how the cell functions? Killed the cell altogether? Using this fluorescent detection, results are immediately visible, simplifying data analysis and instantly narrowing down the pool of candidate compounds. Researchers can use multiple fluorescent labels simultaneously, if each is a unique color, to study multiple molecules of interest at once.
In a way, the compound screening step serves as a crossroads. As researchers begin mapping out their dream drug, this is an opportunity to integrate new technology into their treatment or tweak other treatments to treat this condition of interest. Perhaps the last time your condition of interest got a new drug treatment was thirty years ago. Well, medical technology has advanced quite a lot since then. Can you find a way to utilize that new technology to design or deliver your drug, or to make your candidate compound function in a desirable way? Otherwise, you can look to other conditions’ treatments for inspiration. Drug repositioning is one solution, where researchers see how well a drug treats conditions besides the one it’s made for. Can you model your drug after some highly-effective, cutting-edge drug that treats a completely unrelated condition?
Through compound screening, a combination of data mining, meta-analysis, and a keen eye for detail decrease our number of candidate compounds. It tightens our focus on the compounds that are most likely to interact with the target in the way we want them to. Next, we can put this shortlist of candidates to the test.
Target Validation
After identifying and characterizing the target molecule, we need to validate it. Target validation is a process where scientists conduct experiments on the target to confirm two things. Is the target truly relevant to the condition’s disease pathway? And does modifying the target provide some potential therapeutic benefit for this particular condition?
This is a major elimination round in the drug discovery process. Many hopeful target molecules prove to be less impactful than originally thought. Even if the target is related to the disease pathway, modifying it might not have desirable effects. Sometimes this means that there’s a bigger, badder, more important target molecule out there waiting to be discovered instead.
Target validation encompasses a wide range of experiments. Researchers can use cells to model disease, then evaluate the target’s role in this simulated disease model, similar to HCS. (They may also model a healthy state, to compare the extent of the target’s role in contributing to disease.) To design the most productive drug treatment possible, it’s crucial to understand the biological mechanisms underpinning the disease it treats. Genomic and proteomic studies, such as gene sequencing, can offer valuable insight into how the target molecule expresses genes and proteins. Some experiments even benefit from in silico analysis, which use computer databases and systems to make predictions and visualize data trends.
If these preliminary studies indicate that a candidate compound can modify the target’s function or biological activity, the candidate compound is a hit. And it’s a big deal when it happens.
A hit causes at least one desirable effect on the target, so it could effectively treat the condition. It tells researchers about the candidate compound’s therapeutic potential, while also providing initial clues about its performance and interactions. Hits have the ability to bind with and act upon the target molecule, making them good contenders for drug treatments. And if the candidate compound isn’t a hit, confirming so at this stage saves time and money later on in the drug development process.
At this point, we’re still looking for a needle in a haystack. But as we narrow down our targets into hits, the haystack is dwindling in size, adding momentum to our search.
Hit-to-Lead
A hit’s best shot at becoming a drug is by showcasing its performance in the hit-to-lead (H2L) step. H2L is yet another round of assays, and there are quite a few options for carrying out H2L projects.
Primarily, scientists spend this time learning more about the hits they’ve gathered so far. HTS and in silico screening can make a reappearance here to support these tests. Common properties of a hit that scientists analyze during this step are potency, viability, stability, and affinity or selectivity for various biomolecules involved in the disease pathway. They also typically look at the hits’ pharmacokinetic properties, which indicate how the human body might affect the candidate compounds. How does the body absorb, distribute, metabolize, and excrete the compound? The appropriately-named ADME descriptors tell us how.
Pharmacokinetic assessments paint a realistic picture of what to expect later on in the drug development process, when human subjects will join the studies. Critically, the H2L stage is also when the first evidence of safety (or unsafety) show up. Are there any observable side effects? What about off-target interactions? If they happen, the researchers may need to pivot in their search. And the make-or-break question: can this compound actually, realistically treat the condition of interest?
The objective of this phase is to generate leads, a term for the screening products. Leads are more refined versions of hits, better-understood and ready to be fully studied in vivo (in a living organism). Animal models are commonly used for in vivo studies, since human subjects won’t get involved until the clinical stages of drug development. Before that can happen, researchers have to optimize the best candidates. To prepare the leads for optimization, they lean on the detailed qualitative and quantitative information that they collected during the H2L stage.
Lead Optimization
Now we’re equipped with substantial insight into our leads, the candidate compounds most likely to succeed in humans. To make them suitable for use in humans, first we need to optimize them.
Optimizing leads means enhancing their properties to be more desirable, so the lead will be the best drug possible. This layer of fine-tuning happens as the final stage before drug development. By tweaking the lead’s properties, researchers can set it up for success in the preclinical and clinical trials to come.
Many routes are available here, but oftentimes scientists try to decrease the lead’s toxicity or off-target effects, or increase properties like selectivity or absorption. They also take into consideration the lead’s ADME characteristics, potency, and—above all else—safety profile. To modify these properties, scientists need to tweak the molecule itself. They might alter fundamental characteristics of the lead, like its molecular backbone, or smaller-scale chemical traits, like its functional groups. If the lead has any outlying deficiencies, remedying them at this stage will prevent sunk costs and negative safety impact down the line.
But no drug is perfect. So how do scientists know when a lead is optimized? There’s not necessarily a clear-cut threshold that they adhere to. When the research team is confident that they’ve crafted the lead to be the highest quality it can be, and they’ve minimized any safety concerns as much as possible, then the lead is ready for further development.
Throughout all of these arduous assays, researchers keep an eye out for hints about how the candidate compound might affect the condition of interest. Early indications of the lead’s biological performance can imply whether or not it’s worth pursuing further. Based on these assays’ results, the researchers conclude which candidate compounds are most likely to succeed as possible drug treatments. From here, these leads proceed to the first stages of drug development, which we’ll cover in the next article of this mini-series.
As we can see, drugs proceed through a battery of tests to help researchers identify the cream of the crop. All of this elimination happens well before humans ever come into the picture. Every FDA-approved drug you’ve encountered, every medication on your pharmacy’s shelf, every pill you’ve been prescribed have all undergone this tournament—and won.
How were COVID-19 drugs discovered?
Compared to many other conditions, the drug discovery process for COVID-19 medications happened quite urgently. In light of COVID-19’s detrimental harm to human health, the economy, health care systems, and more, finding an effective treatment—and fast—was of the utmost importance.
This doesn’t mean that the drugs were developed in a reckless or sloppy way, however. Before reaching patients, COVID-19 medications underwent the same regulatory evaluations as any other drug candidate to make sure that they were safe for use. Let’s take a closer look.
How did COVID-19 drug discovery happen so fast?
For some COVID-19 drugs developed in the United States, the FDA employed an Emergency Use Authorization (EUA) to expedite regulatory evaluations. An EUA essentially means that the FDA determined that the benefits of using these drugs outweighed any potential risks, and the drugs would be an important tool in combating the disease. When an EUA is implemented, the drug authorized under the EUA is not FDA-approved yet. However, the FDA still carefully reviews the drug, and deems it a practical enough solution to justify using it during public health emergencies like pandemics. EUAs typically expire when the associated public health emergency ends. (For context, the COVID-19 Public Health Emergency was declared over in the U.S. on May 11, 2023.)
Recall that, under normal circumstances, the drug discovery and development processes can last many years. If some COVID-19 medications hadn’t been authorized under EUAs, patients likely wouldn’t have received these drugs until it was too late. What complicated this even more is the fact that coronaviruses can mutate over time, which might render a once-powerful COVID-19 drug ineffective. Because of this, drug discovery during the pandemic was particularly time-sensitive, more so than the standard drug discovery process.
The fact that the virus can mutate made COVID-19 drug discovery even more purposeful. Mutations in the virus could (and have, to an extent) rendered COVID-19 vaccines less effective than they originally were. But as we’ll see shortly, COVID-19 drugs can target unchanging characteristics of the virus, like how the virus replicates. That basically means that such drugs will always be effective, even if the virus mutates. Scientists developed COVID-19 drugs and vaccines simultaneously, knowing that both would be helpful tools in managing the pandemic.
What’s more, pharmaceutical research (including drug discovery) is a very expensive operation. Given how turbulent the pandemic was, and how it had turned our lives upside-down, it was imperative to find safe, effective COVID-19 treatments in a swift manner. Some funding sources, such as government agencies, temporarily diverted more money than usual toward COVID-19 drug discovery and development efforts. In the U.S., the aptly-named “Operation Warp Speed” propelled these efforts. Having access to these additional funds facilitated the typically slow-moving drug discovery process.
Even as the earliest of these drugs became available, researchers continued searching for additional treatment options while the pandemic raged on. If you come down with COVID-19 now, it’s fairly likely that you could access suitable medications through your health care provider. There are several COVID-19 treatments out there nowadays, but here, we’ll compare and contrast some of the most prominent ones.
Nirmatrelvir/Ritonavir
Among the most widespread COVID-19 medications is nirmatrelvir/ritonavir, marketed as Paxlovid. Its effectiveness derives from its ability to stop the virus from reproducing and spreading further. How does this technique work?
Viruses can’t spread unless they replicate their genomic material first. The virus behind COVID-19 uses a special type of protease to carry out its replication. Proteases are enzymes that break down protein structures. In COVID-19 viral particles, a class of proteases called main proteases (Mpro) take charge of the virus’s replication. Mpro are responsible for splitting long chains of polypeptides at specific cleavage sites. This cleavage leads to several smaller protein molecules, which are precursors in the viral replication process later.
This is where nirmatrelvir/ritonavir comes into play. As an Mpro inhibitor, this medication works hard to interfere with these proteases’ function. Without proteases like Mpro creating the proteins that COVID-19 needs for reproduction, the virus fails to reproduce in an infected person. Since this treatment halts its reproduction, the virus can’t spread to healthy cells in the body, let alone to other people.
As we can tell from the name, nirmatrelvir/ritonavir is a dual drug. The pharmacology sphere refers to dual drugs as synergistic drugs, where combining the drug’s two individual compounds makes the medication more powerful than those compounds are separately. Together, nirmatrelvir and ritonavir make a strong team. Nirmatrelvir is the MVP, actively inhibiting the Mpro enzymes. Meanwhile, ritonavir is in a supporting role. As a pharmacokinetic enhancer, ritonavir gives nirmatrelvir a boost, reinforcing its ability to inhibit Mpro. This happens because ritonavir makes the body metabolize nirmatrelvir more slowly, so nirmatrelvir’s effects last longer.
How was nirmatrelvir/ritonavir discovered?
Although they work great as a pair, each of the two compounds in nirmatrelvir/ritonavir were discovered separately. The ancestor of nirmatrelvir is lufotrelvir, another form of protease inhibitor. Medicinal chemists utilized some savvy synthesis strategies to turn lufotrelvir into nirmatrelvir. In fact, the entire nirmatrelvir molecule is synthetic; it consists of three modified peptides that don’t exist in nature.
Nirmatrlvir’s game-changing feature is its cyano functional group, which replaced lufotrelvir’s phosphate group. The cyano group, a triple-bonded carbon atom and nitrogen atom, reacts with the Mpro molecule at one of its cysteine residue’s thiol group. This reaction represents the interaction between nirmatrelvir and the Mpro; in other words, this is how the drug makes contact with its target. And since it does the actual targeting, the cyano group in nirmatrelvir has another reverent nickname: “the electrophilic warhead.”
Take a moment to recall the ADME properties of a drug: absorption, distribution, metabolism, and excretion. The body absorbs nirmatrelvir and lufotrelvir in different ways. In practical terms, this gives nirmatrelvir a major advantage over lufotrelvir: it can be taken orally. Consuming nirmatrelvir as a pill, instead of in an IV infusion as lufotrelvir requires, makes it a more convenient treatment. There’s no meaningful reason to deliver lufotrelvir in pill form, because lufotrelvir is not orally active. Orally active drugs are ones that the digestive system can absorb, so designing them as pills is a wise choice. The subtle synthetic changes between lufotrelvir and nirmatrelvir are enough to bestow oral activity upon nirmatrelvir.
As for ritonavir, we’ll have to rewind a bit. The final decade of the 20th century saw a growing HIV/AIDS epidemic, and the need for a viable treatment option was growing too. Amid all of its sociocultural impact, AIDS had escalated to become one of the leading causes of death in the U.S.
Cue ritonavir. When it debuted in the mid-1990s, ritonavir was a protease inhibitor for HIV-1, one of the viruses causing HIV. Starting from the precursor, an inhibitor called A-80987, it only took small modifications to create ritonavir. For example, ritonavir got two thiazole rings (five-membered rings containing a sulfur, a nitrogen, and two double bonds) to enhance its stability. Compared to A-80987, ritonavir has greater potency and, perhaps most important of all, high selectivity: it binds very precisely to HIV proteases to prevent them from cleaving into functional proteins. This mechanism of action bought time for scientists and public health experts to manage the epidemic and pursue a cure.
Optimizing these pharmacokinetic properties made ritonavir a superpower in the fight against HIV/AIDS. When COVID-19 surfaced, existing drugs like ritonavir were a promising solution due to these properties and their role in preventing viral replication. Remdesivir is also orally active, so packaging it in the same pill capsule as nirmatrelvir is an easy way to deliver the drug. Alone, ritonavir doesn’t treat COVID-19 in any significant way, and nirmatrelvir wouldn’t have as big an impact. But by joining forces as a synergistic drug, both compounds can work together to fight off the virus.
Remdesivir
In the roughly 15 years since its introduction, remdesivir (branded as Veklury) has been repurposed for several conditions. COVID-19 is among the latest of these, after the drug failed against hepatitis C and RSV but showed some success in fighting the Ebola virus.
During the COVID-19 pandemic’s early growth, researchers already knew two key points. First, that COVID-19 is caused by a coronavirus called SARS-CoV-2. Secondly, that coronaviruses are RNA viruses, so their genetic material is RNA rather than DNA. SARS-CoV-2 viral particles use the RNA-dependent RNA polymerase (RdRp) enzyme to reproduce themselves. Polymerases like RdRp allow the virus to replicate its own genome, so disrupting RdRp’s function prevents any replication.
As RdRp builds a copy of the virus’s RNA, remdesivir binds to the RNA. After binding, the RdRp can only add three further nucleotides to the RNA strand. Replication stops after this point due to steric hindrance between the remdesivir molecule and the RNA strand’s nucleotides. Any attempt to replicate SARS-CoV-2’s genome will be incomplete. This disruption stops viral spread cold in its tracks, even in an infected person. That’s key to interrupting a pandemic, especially one spreading like wildfire, as COVID-19 did in waves.
How was remdesivir discovered?
Remdesivir wasn’t initially designed to treat COVID-19, but its origin story still revolves around the idea of pandemics. It started when the pharmaceutical company Gilead Sciences joined forces with the U.S. Centers for Disease Control and Prevention (CDC) and the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID). Together, these three organizations sought treatment options for RNA viruses that pose the potential threat of causing pandemics. (This includes the viruses behind outbreaks like SARS and MERS, which arise from close cousins of SARS-CoV-2.)
With the goal of creating a shortlist of possible drug candidates, these organizations’ scientists referenced an existing chemical library. These libraries can classify chemical compounds according to the reactions and interactions they have. Early on in drug discovery, this information provides insight as to how a specific compound would behave if used as a drug ingredient. This library included compounds known to have some antiviral function against RNA viruses, so it easily set the screening process in motion.
Libraries like the one used to discover remdesivir are solid starting points to discover drugs against RNA viruses, like SARS-CoV-2. Clinical trials of remdesivir as a COVID-19 treatment began shortly before the disease was declared a pandemic, positioning the drug as a front runner in the evolving outbreak. As the first FDA-approved drug for COVID-19, it wasn’t long before remdesivir became a go-to treatment on the international stage.
Nirmatrelvir/ritonavir and remdesivir each attack COVID-19 at its source, targeting slightly different points of the viral life cycle. Whereas remdesivir impedes the virus’s ability to replicate its genome, nirmatrelvir/ritonavir impedes its ability to produce crucial peptides. These three compounds illustrate how drug discovery can take many diverse paths: lead optimization, drug repositioning, compound screening, chemical synthesis, and more.
Conclusion
In the biopharmaceutical realm, the drug discovery process lays the groundwork for a candidate compound’s subsequent development and clinical research. Drug discovery commences by identifying at least one target molecule, a molecule the drug will bind to and change. Scientists screen candidate compounds against targets to pinpoint potential matches, or hits, and test the validated targets through laboratory assays. Some of these hits get refined and become leads, only a fraction of which will go on to get optimized and developed. This intricate, hyper-focused process was the foundation for discovering COVID-19 drugs like nirmatrelvir/ritonavir and remdesivir, emphasizing its utility for our future public health approaches.