Faced with the biggest global pandemic in most of our lifetimes, all around the world research teams are working hard to provide treatment options and/or a vaccine for the novel coronavirus (COVID-19) disease. With economies shut down, workers furloughed and children staying home from school, the race to find a golden bullet to help to end the lockdown and provide certainty, or at least comfort, is a vital scientific endeavour.
Some programmes are highly specific to COVID-19. For example, vaccines are designed not just for a particular illness, but for that strain of that illness, which means they must be created de novo in the face of the novel coronavirus.
By contrast, treatment of the disease may not necessarily require a new drug or chemical compound. It may be possible to treat COVID-19, either to “cure” or to alleviate symptoms to assist the body’s natural fight back, using agents already available to us. This blog looks at how this might work, why it is advantageous, and at some of the work being done by hardworking teams.
Drug repurposing
There has been widespread discussion both in the news and some government briefings about so-called drug repurposing. Put simply, this is testing drugs already prescribed to patients for other diseases for efficacy in the treatment of COVID-19. The advantage of this approach is that, because the drugs are already used widely in the population, their safety and side effects are well-understood. Of course, clinical trials are still needed to determine the drug’s usefulness for this disease, but the process to approval and use is considerably shortened.
There has been much interest in so-called anti-viral agents. That is, drugs which are approved and used to treat viruses like influenza, HIV, and hepatitis. This is unsurprising because COVID-19 is also caused by a virus (SARS-CoV-2), and there are similarities in how viruses replicate and colonise. As the pandemic gained hold in Asia, stories emerged of medics trying various approved antiviral agents, often as treatments of last resort, with some reported success.
Solidarity trials
The World Health Organisation (WHO) is presently coordinating four “Solidarity” trials – massive clinical trials for four promising treatment regimens. These Solidarity trials will be carried out at hospitals around the world and eligible patients, with their consent, will be randomly allocated to one of the local standard of care treatment, or one of the four treatment regimens of interest.
Perhaps the most talked about of these regimens is chloroquine, an anti-malarial agent that has been used by some medics with reported success, and the related compound hydroxychloroquine. One of these agents is used. There is pharmacological modelling to indicate that hydroxychloroquine may be a useful prophylactic agent for COVID-19, and may inhibit viral shedding of SARS-CoV-2. If confirmed in patients this will be promising as ultimately reducing transmission rates will be key to controlling COVID-19.
Other Solidarity trials are directed to Remdesivir, which was used in fight against Ebola, the combination of Lopinavir and Ritonavir, which is approved for the treatment of HIV, and Lopinavir/Ritonavir with interferon beta-1a. Investigations into the efficacy of other approved antiviral drugs against SARS-CoV-2 are also being reported, along with widespread screening of other drugs presently prescribed for all manner of diseases. We await the results of these investigations with interest, noting of course that suitability of patients and dosage regimens will need to be determined by science and medical professionals.
Compound libraries
However, already-prescribed drugs aren’t the only tools available. Alongside these investigations, there is a huge amount of work going into screening compound libraries in the search of potentially useful molecules. In the rest of this blog we’ll look at compound libraries: what they are, how they can be useful, and some of the efforts in this area in the fight against COVID-19.
When we pop a pill from a blister pack, or watch a drug being hooked up to an IV drip, most people give little thought to the vast amount of research behind the product. However, it is the initial stages of that research that are now of particular interest in the search for COVID-19 treatments. Something that is often given no attention may ultimately help to solve our problems.
It is estimated that as many as 5,000 to 10,000 structures may be made in the development of a new small molecule drug. Large numbers of molecules are synthesised and screened for efficacy against the target, and from that initial screening work comes a better understanding of the structure activity relationship to the target. In other words, which modifications make a compound better, or worse? More compounds may be made and tested, until the number of compounds of interest is whittled down to just a dozen or so which can enter pre-clinical testing. From these, a candidate is selected and the formulation and dosage determined. It enters clinical trials and, if successful, is approved and prescribed to patients.
This process is typically reflected in the patent applications that we see filed to cover a drug. The initial patent applications typically cover an area of chemical space. That is, the claims are directed a certain structural backbone while permitting variation at points around the structure. Such patent applications often contain tens, if not hundreds, of examples and preliminary biological data, for example IC50 values. Later patent applications are usually directed to a smaller subset of that chemical space – a so-called selection – and focus in on the most promising structures, with only limited variation and a smaller number of examples and more detailed biological data. Even later in the process, patent applications may mention only the lead compound, or the lead compound and a small number of back up compounds.
The process of selecting a candidate from scratch takes about 3 to 6 years, and much of this time is taken up making the compounds themselves. Teams of skilled medicinal chemists design structures and then make the compounds, often from basic reagents in multistep reaction sequences. It is not always easy to make a new chemical structure.
These compounds, even though discounted for the project at hand, form libraries along with the information about to make them, characterisation data and biological data. It is to these libraries that some projects have now turned in the quest for COVID-19 treatments, with numerous pharmaceutical companies screening their own libraries and/or offering access to other research projects.
The quest for COVID-19 treatments
For example, Exscalate4CoV is a project funded by the European Commission to screen in silico molecular structures from various libraries against the crystal structure of SARS-CoV-2. The system is reported to have the capability to virtually screen three million molecules per second in an effort to find those that bind best to the most ‘druggable’ sites on the surface of the coronavirus. Put simply, the computer tries to determine which molecular structures fit into active “pockets” on the virus’ structure. As each of these molecules has already been made and characterised, the process of (re)making and testing any promising hits in vitro should be considerably shortened compared to a novel structure.
Although vast in its scope, Exscalate4CoV is only one of many screening programmes taking place. For example, Boehringer Ingelheim has announced computational screening of its entire library of more than one million compounds with the aim to identify novel small molecules with activity against two priority viral targets: SARS-CoV-2 main protease and SARS-CoV-2 papain-like protease, while numerous other pharmaceutical companies have announced collaborations with other companies, universities and initiatives to screen their libraries.
One such initiative, the COVID-19 Therapeutics Accelerator, is investigating this same approach, partnering with pharmaceutical companies who bring their compound libraries and clinical data to the collaboration and will lend the commercialization and other expertise that will be required to scale up successful drugs. The initiative was seed funded by The Bill & Melinda Gates Foundation, Wellcome, and Mastercard, and further funding has been made available by the U.K. government and The Chan Zuckerberg Initiative.
All around the world similar programmes are taking place, both collaboratively and in house, with the same goal of finding promising molecules and accelerating through that typical 3 to 6 year process to identify a candidate. Libraries of compounds that were dismissed as not useful are now being mined as a valuable resource in the fight to control COVID-19 and return to normality, and work most of us never even consider en route to the drugs that make the headlines may now come into the spotlight.
We wish all of the teams working on these projects success!
This blog was originally written by Sarah Kostiuk-Smith
